PNH PNH PNH 3/22/2016 PNH. Paroxysmal Nocturnal Hemoglobinuria (PNH): Current Thinking on the Disease PATHOGENESIS OF PNH

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1 3//1 PATHGENESIS F PIG-A gene Bone Marrow Failure Disease Scientific Symposium Rockville, March 17-1, Paroxysmal Nocturnal Hemoglobinuria (): Current Thinking on the Disease PRTEIN glycosylphosphoinositol (GPI) anchor NH Extracellular space Rodrigo T. Calado, MD/PhD 9 C NH CH CH P MAN(a 1-) MAN GLYCAN CRE CH Ribeirão Preto School of Medicine University of São Paulo (a 1-) MAN GLU N PHSPHATIDYL -INSITL Cytoplasm PHSPETHANLAMINE P INS CH CH CH C C CH GPIAnchored Transmembrane GPI-anchored protein a C C3 X CD59 C3b CD55 b C3 conv x 1 15 CD59 Absent CD55 - higher C3 Absent CD55 - higher C3 Absent CD59 MAC formation b,,7 Normal red blood cells are protected from complement a C CD55- and CD59-negative RBCs are destroyed x 1 15 Complement Activation b Intact Red Blood Cell Absent CD55 - higher C3 Absent CD59 MAC formation b,,7, paroxysmal nocturnal haemoglobinuria b-9 b- b-9 Free hemoglobin Reduction in circulating RBC mass Anemia b- 1. International Interest Group. Blood. 5;1: Brodsky R Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 5; Rother RP et al. JAMA. 5;93: Socie G et al. Lancet. 199;3: Hill A et al. Br J Haematol. 7;137:

2 3//1 is a Progressive Disease of Unregulated Complement Activity clone expansion Normal red blood cells are protected from complement attack by a shield of terminal complement inhibitors Without this protective complement inhibitor shield, red blood cells are destroyed Renal Failure Pulmonary Hypertension Significant Impact on Survival Complement Activation Abdominal Pain Dyspnoea Intact RBC Hemoglobin released from destroyed RBCs Anaemia and release of free Hb Fatigue Dysphagia Haemoglobinuria Significant Impact on Morbidity A Hill, Leeds N Erectile Dysfunction clone expansion Defining Patients with Classical haemolytic patients associated with AA or MDS also with Haemolysis rgan impairment due to haemolysis Cytopenia Aplastic anemia > AA syndrome > Hemolytic Cytopenia Low level of Hemolysis Cytopenia Hemolysis 9 PARXYSMAL NCTURNAL HEMGLBINURIA () TRIAD F CLINICAL FEATURES 1. somatic mutation of PIG-A in an hematopoietic stem cell Hemoglobinuria Budd-Chiari Syndrome Aplastic Anemia. aborted GPI anchor synthesis 3. absent cell surface GPI-anchored proteins. clonal expansion of GP-AP deficient cells = Intravascular Haemolysis Disabling Symptoms - Abdominal pain - Dysphagia - Erectile failure - Severe lethargy Liver, cerebral 5% of patients; fatal in 33% Bone Marrow Failure ften precedes Selects for clone hemolysis (CD59-) BM failure (?) thrombosis (?)

3 3//1 ECULIZUMAB (ANTI- ANTIBDY) human framework regions TRIUMPH Transfusion Reduction Efficacy and Safety Clinical Investigation, Randomized, Multicenter, Double-Blind, -Controlled, Using in Paroxysmal Nocturnal Hemoglobinuria human IgG heavy chain constant region 1 and hinge Hinge CH CH3 complementarity determining regions (murine origin) human IgG heavy chain constant regions and 3 Hemolytic transfusion dependent patient bservation qualifying transfusion Up to 3 months R months Extension Study + months TRIUMPH ENTRY CRITERIA Inclusion criteria: 1 years-of-age episodes of transfusions in the previous 1 mos type III erythrocyte population 1% Platelets 1,/mm 3 LDH 1.5 times ULN Exclusion criteria: Transfused with Hb >1.5 g/dl in prior year Complement deficiency Active bacterial infection Prior meningococcal disease Pregnancy TRIUMPH STUDY DESIGN Dosing schedule: iv infusion of eculizumab over 3 min Induction period mg every 7± days for doses Maintenance period 9 mg 1 week later, followed by 9 mg every 1± days for a total of weeks Concomitant medications: No change in immunosuppressant drugs, steroids, anti-clotting agents or hematinics Patients were vaccinated against Neisseria meningitidis TRIUMPH ENDPINTS TRIUMPH PATIENT RECRUITMENT Co-primary endpoints: Stabilization of Hb levels: Hb value above the Hb set point without transfusions for entire trial period Units of PRBCs transfused Secondary endpoints: Hemolysis: lactate dehydrogenase (LDH) AUC Fatigue assessed via the FACIT-Fatigue instrument Exploratory endpoints: QoL measures including fatigue (ERTC QLQ-C3) Safety reporting *Value at which each patient received a qualifying transfusion 3 Received eculizumab Discontinued treatment 1 inconvenience of travel 1 pregnant 3 Analyzed 115 Assessed for eligibility Enrollment 7 Randomized and received treatment Allocation Follow-up Analysis Excluded ( patients) Failed inclusion criteria 1 Failed observation period 1 Randomization error Received placebo 1 Discontinued treatment Lack of efficacy but monitored for duration of study Analyzed 3

4 Functional Symptoms/Items LDH (IU/L) Stabilization of Hb, % patients Patients Avoiding Transfusion, % 3//1 EFFECT F ECULIZUMAB N HEMLYSIS LDH Normal Screening P<.1 EFFECT F ECULIZUMAB N TRANSFUSINS Co-Primary Endpoint (1) Median Transfusions Mean Transfusions 1 1 P< Pre- Trial Pre- Trial Pre- Trial Pre- Trial EFFECT F ECULIZUMAB N STABILIZATIN F HEMGLBIN LEVELS Co-Primary Endpoint () 5 P<.1 EFFECT F ECULIZUMAB N TIME T FIRST TRANSFUSIN % Reduction in PRBC Units Transfused 5 51% 3 P< % EFFECT F ECULIZUMAB N QL Global Health Status Role Social Cognitive Physical Emotional Fatigue Pain Dyspnoea Appetite Loss Insomnia Financial Difficulties Constipation Nausea/Vomiting Diarrhoea Favors Favors *Mixed model analysis 5-1 point change is considered clinically meaningful Difference P Value* <.1 <.1 =.3 =. <.1 =. <.1 =. <.1 <.1 =.1 =.1 =.199 =.5 =.17 soba D et al. J Clin ncol. 199;1:139, Brodsky RA et al, Blood ; 111:1 ECULIZUMAB: IMMUNGENICITY: HAHA (HUMAN ANTI-HUMAN ANTIBDIES) Timing IgG First dose / (%) / (%) Week 1 /1 (%) / (%) Week 1/39 (.5%) 1/3 (.3%) IgM First dose / (%) / (%) Week 1 /1 (%) / (%) Week / (%) / (%)

5 LDH (IU/L) U/L g/dl K/uL 3//1 EFFECT F ECULIZUMAB N HEMLYSIS LDH EXTRAVASCULAR HEMLYSIS IN UNCVERED BY ECULIZUMAB TREATMENT 1 1 Corticosteroids 5 mg Pregnancy Hemoglobin 15 1 P< Reticulocytes 5 Normal LDH Screening u prbc u prbc ECULIZUMAB REDUCES THRMBSES IN Combined data from TRIUMPH, SHEPHERD, UK cohort, and phase III extension study compared to pre-treatment events Pre-rx: 1 thrombotic events in 195 patients (13 on anticoagulation) TE events: pre-rx = 7.5 vs post-rx = 1./1 patient years (% reduction) ECULIZUMAB (SLIRIS) IN PRACTICE Advantages Dramatically reduces intravascular hemolysis and related symptoms (anemia and N-induced) May be effective in preventing thrombosis without bleeding risk Well tolerated Disadvantages Expensive (!) Risk of specific infections with Gram- cocci Life-long infusions Unmasked extravascular hemolysis in some cases Hillmen P et al, Blood, 7 5