3/6/2017. Prevention of Complement Activation and Antibody Development: Results from the Duet Trial
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1 Prevention of Complement Activation and Antibody Development: Results from the Duet Trial Jignesh Patel MD PhD FACC FRCP Medical Director, Heart Transplant Cedars-Sinai Heart Institute Disclosures Name: Jignesh Patel, MD PhD, Cedars-Sinai Heart Institute, CA, USA Commercial Interests & Nature of Relationships: Alexion Pharmaceuticals: Research Grant Support, eculizumab in heart transplantation I will discuss off label use and investigational use of the following drugs: Rituximab, bortezomib, eculizumab Antibody Mediated Rejection(AMR) an emerging problem The problem of AMR remains unsolved as current immunosuppressive regimens are largely intended to interfere in T-cell signaling pathways. 1 As a result, AMR continues to appear in upto 10-20% of heart transplant patients 2 (1)ColvinRB, et al. Nat Rev Immunol. 2005;5: (2) MichaelsPJ, etal. J Heart Lung Transplant. 2003;22:
2 Antibody Mediated Rejection(AMR) an emerging problem 2012 OPTN/SRTR Annual Report The Challenge of the Sensitized Patient.. Pre-transplant Limited donor pool Prolonged (prohibitive) time on wait-list Increased wait-list mortality After transplant increased risk of rejection graft loss development of allograft vasculopathy DSA+ DSA OPTN/SRTR Annual Report Ho EK et al. Hum Immunol Jan;72(1):5-10 Kaczmarek et al.;exp Clin Transplant Sep;6(3): P =.025 Mechanisms of Donor-specific Antibody-mediated Endothelial Injury Farkash, E. A. & Colvin, R. B. (2012)Nat. Rev. Nephrol.doi: /nrneph
3 Accommodation Accommodation is the absence of humoralmediated injury and continued function of a graft, despite the presence of anti-donor antibodies in the circulation. The difference between accommodation and antibody mediated rejection (AMR) appears to be the level of complement activation 1. 1 Williams et al. Transplantation. 78(10): , November 27, Activation of Complement in AMR and Accommodation In an experimental model of cardiac xeno-transplantation 1, grafts with AMR showed deposition of all complement components, including C4d and C5b- C9 MAC. However, xenografts demonstrating accommodation showed C4d deposits only. Inhibition of C5b-C9 MAC and C5a generation could potentially act as a strong promoter of accommodation. AMR 1 Williams et al. Transplantation. 78(10): , Drugs Targeting the Complement Cascade 1Purified proteins, 2monoclonal antibodies, 3engineered proteins, 4small molecules, Thurman JM, Le Quintrec M, Kidney International,
4 Eculizumab Eculizumab is a humanized monoclonal antibody that binds to and subsequently prevents activation of complement component C5 by the amplified C3 convertase molecules. C4d Eculizumab is approved by the US Food and Drug Administration for treating paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (HUS). Eculizumab X Anaphylotoxin Eculizumab Experience in Renal Transplant Patients 26 highly sensitized pts with positive cross-match underwent desensitization with plasmapheresis + IVIG and treated with eculizumab after renal transplantation. After 3 months follow-up, the study group compared to historical controls (n=51) had less AMR (7.7% vs. 41.2%, p=0.003). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplant that caused proximal complement activation. Stegall M. Am J Transplant 2011;11: The DUET* Cardiac Trial TRIAL OBJECTIVES AND PURPOSE Investigational pilot trial to determine the safety and efficacy of the de-novo use of eculizumab to prevent symptomatic antibody (AMR 1) and/or cellular mediated rejection ( 2 Grade 2R) in highly sensitized cardiac transplantation recipients (PRA>70%). clinicaltrials.gov NCT *The De-novo Use of Eculizumab Alongside Conventional Maintenance Therapy in Presensitized Patients Receiving Cardiac Transplantation: An, Open-Label, Investigator-Initiated Pilot Trial: [The DUET Cardiac Trial] 4
5 DUET: Outcomes A. Safety: Incidence of hospitalization due to intravenously treated infections in the 1 st year B. Tolerability: Incidence of patient withdrawal or loss to followup C. Efficacy: Outcomes determined included : 12 month actuarial survival 12 month freedom from antibody mediated rejection (AMR 2) 12 month freedom from cellular rejection (ACR 2R), 12 month freedom from any treated rejection (ATR), 12 month freedom from graft dysfunction and treated infection. Protocol Eculizumab Protocol: Meningococcal vaccine 2 weeks prior to transplant or Gram Neg antibiotic prophylaxis Methylprednisolone IV, Anti-thymocyte globulin (ATG) 1.5 mg/kg x 5 days followed by IVIG 1 gm/kg x 2 days Eculizumab Day 0: 1200 mg Day 1,7,14,21: 900 mg Day 28,42,56: 1200 mg Tacrolimus, mycophenolate, prednisone Demographics (N=14) Mean recipient Age, Year ±SD 49.5 ±12.3 Mean Donor Age, Years ±SD 31.9 ±11.4 BMI, Mean ± SD 25.3 ±3.7 Female (%) 85.7% (12/14) Previous Pregnancy in Females (%) 91.7% (11/12) Ischemic Time, Mean Mins ± SD ±52.1 Primary Reason for Tx, Underlying Diagnosis of CAD (%) 14.3% (2/14) Status 1 at Transplant (%) 100.0% (14/14) CMV Mismatch (%) 14.3% (2/14) Diabetes Mellitus (%) 42.9% (6/14) Treated Hypertension (%) 57.1% (8/14) Prior Blood Transfusion (%) 66.7% (8/12) Pre-Transplant cpra, Mean ± SD 83.8 ± 22.6 Pre-Transplant Creatinine Mean ± SD 1.5 ±0.6 Insertion of MCS Device 50.0% (7/14) 5
6 Prior Desensitization Therapies Therapy N=14 Bortezomib + Plasmapheresis 64.2%(9/14) Bortezomib + Plasmapheresis + IVIG 7.1% (1/14) IVIG + Plasmapheresis 7.1% (1/14) None 21.4% (3/14) Prospective Donor-Specific Crossmatch Results at Transplant Crossmatch Type Results, N=14 T-Flow Cytometry Crossmatch 93.1 ± MCS B-Flow Cytometry Crossmatch ± MCS T-Cell Complement-Dependent Cytotoxicity Crossmatch B-Cell Complement-Dependent Cytotoxicity Crossmatch All negative All negative Positive T-Flow >50 MCS Positive B-Flow >100 MCS Preliminary Outcomes Endpoints N=14 1-Year Actuarial Survival 92.8% 1-Year Actuarial Freedom from Cellular Rejection (ISHLT 2R) 1-Year Actuarial Freedom from Antibody-Mediated Rejection (AMR 2) 1-Year Actuarial Freedom from Any Treated Rejection 100.0% 76.8% 86.9% Average 6-Month Left Ventricular Ejection Fraction (%)* 64.4 ± 8.1 % of Patients with DSA at 1 Month Post-Transplant 71.4% (10/14) 1-Year Freedom from Treated Infection 58.6% * No patient with reduced LVEF 6
7 DSA Post-Transplant Patient Number of DSAs within 1-Month Post- Number of DSA within 1-Month w/ Overall # DSA Post-Transplant (Class DSA Present Transplant (Class I/II) MFI >5000 (Class I/II) I/II) (N=11/14) (N=8/14) (N=11/14) 1 Y 8 (5/3) 2 (1/1) 9 (5/4) 2 N 3 Y 1 (1/0) 0 (0/0) 1 (1/0) 4 N 5 Y 2 (0/2) 2 (0/2) 2 (0/2) 6 Y 6 (2/4) 4(0/4) 6 (2/4) 7 Y 4 (2/2) 3 (1/2) 4 (2/2) 8 Y 4 (1/3) 1 (0/1) 4 (1/3) 9 N 10 Y 1 (1/0) 1 (1/0) 1 (1/0) 11 Y 3 (3/0) 2 (2/0) 3 (3/0) 12 Y 1 (0/1) 0 (0/0) 1 (0/1) 13 Y 1 (0/1) 1 (0/1) 1 (0/1) 14 Y 1 (0/1) 0 (0/0) 1 (0/1) Positive Crossmatch Kidney Transplant Recipients Treated With Eculizumab: Outcomes Beyond 1 Year Cornell et al. American Journal of Transplantation 2 MAR 2015 DOI: /ajt Transplant Glomerulopathy at 1 year: Impact of DSA levels Cornell et al. American Journal of Transplantation 2 MAR 2015 DOI: /ajt
8 Drugs Targeting the Complement Cascade Thurman JM, Le Quintrec M, Kidney International, Purified proteins, 2monoclonal antibodies, 3engineered proteins, 4small molecules, 5small interfering RNA. Effects of C1-Esterase Inhibitor C 1s + C 1r C1 Classical Pathway LPS C1-INH Lectin Pathway Mannan-binding lectin associated serine proteases P-Selectin E-Selectin Inflammation Vascular Permeability Hereditary Angioedema Effect of C1 Inhibition on C1q+ Abs After Renal Transplantation Vo A et al. Transplantation. 99(2): , February
9 C1 Inhibition for Treatment of Renal AMR 18 pts with mild-moderate AMR treated with plasmapheresis/ivig and randomized 1:1 to c1 esterase inhibitor (Cinryze) Treatment well tolerated No difference in d29 pathology or graft survival C1-INH group showed a trend in sustained improvement in renal function at d90 At 6 months 0/7 pts in C1-INH group and 3/7 in control group showed transplant glomerulopathy Endogenous c1-inh levels reduced in control group after plasmapheresis but remained supraphysiological in the c1-inh group Montgomery et al. AJT June 2016 Conclusions The ongoing DUET pilot study suggests terminal complement inhibition with eculizumab facilitates heart transplantation in high risk highly sensitized patients with acceptable outcomes at 1 year. Eculizumab appears to facilitate heart transplantation despite the presence of DSA even at moderate or higher MFI Eculizumab appears to be well tolerated and is associated with a low rate of infection Further studies are needed to confirm these preliminary results and determine effects on development of CAV Early results in renal transplantation show some promise with c1 esterase inhibition 9
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