European Phase 3 Studies with Pathogen-inactivated Red Blood Cells:

Transcription

1 European Phase 3 Studies with Pathogen-inactivated Red Blood Cells: William Reed, MD Director, Clinical Research and Medical Affairs London September, 2012 BE SURE.

2 Objectives Rationalle & brief background Successful Phase 1/2 study 2011 Design of phase 3 studies in Europe: thalassemia major Plans in the US BE SURE. 2

3 Crucial Modern Pattern in SCD " Patients diagnosed earlier Newborn screening " Better medical interventions Parent education, PCN, febrile illness, spleen size, etc. " Patients living longer: chronic complications " More transfusion needed blood safety and availability BE SURE.

4 PI RBC System " Reduce risk for transfusion transmitted infection (TTI) " Complete PI for main 3 components " Very low plasma content (Tx reactions, TRALI) " Replace gamma irradiation and avoid damage to the RBC caused by gamma " Enable wider and safer use of chronic transfusion " Provide better characterized RBC component: Hb and Fe content BE SURE.

5 Transfusion-transmited Babesiosis in the US Herwaldt BH, 2011 Ann Int Med cases from with a 19% fatality rate BE SURE.

6 Transfusion-transmited Babesiosis in the US Herwaldt BH, 2011 Ann Int Med cases from with a 19% fatality rate BE SURE.

7 US Babesiosis 10 new cases BE SURE. 7

8 Supplement to Transfusion BE SURE.

9 INTERCEPT RBC: Mechanism of Action " S-303 is a nucleic acid-targeted alkylator that quickly diffuses into viruses, bacteria, parasites and blood cells and is designed to react quickly and decompose " Glutathione (GSH) is used to quench side reactions of the effector with other biological materials

10 Second Generation INTERCEPT RBC Clinical Process

11 Pathogen Inactivation Process Optimization: Reduce interaction of S-303 with RBCs and improve process flexibility " First Generation Process 0.2 mm S mm GSH (acidic) Compound adsorption device to remove residual S-303 Erythrosol storage solution " Second Generation Process 0.2 mm S mm GSH (Na salt) Diluent solution for PI Removal of treatment solution and replacement with storage solution Approved RBC storage solutions

12 Pathogen Inactivation Efficacy Evaluations Pathogen Mean Log Reduction* Pathogen Mean Log Reduction** First generation system Plasmodium falciparum >6.8 Babesia microti, >4.9 Trypanosoma cruzi >5.3 West Nile virus >6 Second generation system tube study XMRV >4 *n=1-3 RBC units or tubes S. aureus 5.1 ± 0.3 S. marcescens 5.1 ± 0.1 Y. enterocolitica 6.8 ± 0.2 E. coli 6.7 ± 0.1 HIV >5.9 ± 0.1 Bovine viral diarrhea virus >4.8 ± 0.1 Blue Tongue 5.0 ± 0.4 Adenovirus Type 5 >7.4 ± 0.2 **Second generation process, n=4 full RBC units

13 NEW Phase 1 Study, Second Generation: In Vitro RBC Characteristics-- Day 35 (n=27) Attribute Test Control Total Hemoglobin (g/unit) ± 3.6 Not measured Hemolysis (%) ± ± 0.13 Spun Hematocrit (%) ± 2.4* 62.4 ± 3.6 ATP concentration (mmol/g 3.34 ± 0.80* 3.59 ± 0.81 Hb) 2 ph (at 37 o C) ± 0.039* ± Extracellular Potassium (mm) ± 3.6* 52.7 ± Measured prior to storage 2 Measured after 35-days of storage * p-value <0.05 " The total hemoglobin, hemolysis and hematocrit meet the requirements for leukoreduced RBC in additive solution " The ATP concentration is well over the critical threshold of 2.0 mmol/g Hb (ref.) Ref: Hess JR, Greenwalt TG. Transf Med Rev., 16 (4), (2002).

14 NEW Phase 1 Clinical, Second Generation: 24- Hour Recovery meets FDA Requirements (n=27) 24-hour Recovery (%, Dual Label, Cr-51 and Tc-99m) Subjects with Dual Label Recovery < 75% Median Lifespan (T 50, days) Test Control 88.0 ± ± ** 39.5 AUC (% of cells surviving) 22.0* 23.9 * p<0.05, ** p<0.001 " The 24-hour recovery was similar between groups and met FDA criteria " The median lifespan,t50, of Test RBC was within the reference range of 32 to 37 days using 51 Cr label Cancellas et al. Transfusion 2011

15 Clinical Studies " Europe: Acute and chronic anemia separately Chronic anemia thalassemia major Acute anemia cardiac surgery " US: thalassemia and sickle cell anemia Chronic transfusion Final design will require Hgb increment data from Europe and US

16 Italian Thalassemia Study S-303 treated RBC components Investigators: R Galanello Cagliari (Sardinia) A Piga - Torino 16

17 Purpose " Phase 3 study of efficacy and safety of RBC components prepared using the S-303 system for PI compared with conventional RBC components " Thalassemia patients represent the most transfusion-exposed patient group today 17

18 Design " Randomized, controlled, double blind, crossover study to evaluate both efficacy and safety of S 303 treated RBC components in 70 subjects " 4 transfusion cycles for Test and 4 for Control 2 additional wash-n cycles for each period " Statistical hypothesis of non-inferiority " Non-inferiority margin of 15% 18

19 Italian Thalassemia Study Transfusion-dependent thalassemia major patients (n = 70) 1 efficacy endpoint = Hemoglobin usage 1 safety endpoint = Immunogenicity with repeat exposure Screen, randomize n=25 n=25 INTERCEPT 2 txns* 4 txns 2 txns* Control 4 txns Control 2 txns* 4 txns 2 txns* 4 txns INTERCEPT Each patient is on study ~9-12 months * Patients receive 2 wash-in transfusions followed by 4 transfusions of INTERCEPT or control. 19

20 Primary Efficacy Endpoint " Hb consumption adjusted for body weight and time of observation (total gm Hb/Kg/d) " Analogous to cc/kg/day of PRBC adjusted to 100% Hct 20

21 Secondary Efficacy Endpoints " Hb increment 1-h post-tx (Adjusted for mass of Hb transfused and body weight) " Hb percent decline per day 21

22 Primary Safety Endpoint " Incidence of a treatment-emergent antibody with confirmed specificity to S 303 treated RBC associated with clinically significant accelerated RBC clearance " Protocol defines precisely how to detect the Ab and criteria for accelerated RBC clearance (Sections and 8.4.2) 22

23 Secondary Safety Endpoint " Adverse events " Transfusion reactions within 24 hours of a study transfusion with the assigned study product " Frequency of allo immunization to RBC allo-antigens 23

24 Inclusion criteria " Age 10 years, of either gender " Diagnosed with thalassemia major and currently participating in a chronic transfusion program " Have at least a 1 year history of chronic RBC transfusion support with a stable transfusion requirement (per treating physician) " Transfusion cycle >/= 14 days " All RBC components given on the same day for a given transfusion cycle " Have a negative direct antiglobulin tests (DAT) " Stable iron chelation regimen " Available for hemoglobin testing at 1 hour posttransfusion " Signed and dated informed consent 24

25 Exclusion criteria " Baseline positive antibody test specific to S 303 treated RBC " Evidence of splenic hyper function defined as a transfusion requirement >180 cc/kg/year " Splenic enlargement: palpable 4 cm or more below the costal margin " Pregnant or breast feeding female, or female of child bearing potential not using a medically approved form of contraception " Acute or chronic medical disorder that, in the opinion of the investigator or medical monitor, may prevent the subject from completing participation in the study " HIV or HCV infection (defined as RNA positive) " Alloimmunization to minor blood group antigens to the extent that the ready provision of compatible blood may not be feasible for the study (alloimmunization alone is not an automatic exclusion) " Treatment with any medication that is known to affect RBC viability " Current specialized treatment with washed or frozen RBC " Requirement for gamma irradiated RBC components (would present blinding difficulty due to blood component labeling regulations) " Participation in another clinical study, either concurrently or within the previous 28 days, in which the study drug or device may influence red blood cell viability 25

26 Ab Specific to S-303 Treated RBC " Panel of reagent RBC S-303 treated and non-treated from same donors " Positive reaction (gel card) in 3 of 3 S-303 treated reagent cells AND non-reactive with untreated reagent cells " Specificity confirmed by a second high specificity technique (inhibition titration) " This establishes the presence of specific Ab BUT does not establish its clinical significance 26

27 Clinical Significance of Ab specific to S-303 treated RBC: all required " Investigator judges the event an HTR " Presence of specific Ab confirmed by a second inhibition technique (specificity) " Ab active at 37 C (appropriate thermal amplitude) " If DAT is positive, then specific Ab identifiable in the eluate from the subject s RBC " Plus any one or more of the following: Week 1 post-transfusion: loss of >50% of the 24-h posttransfusion increment Week 2 post-transfusion: loss of 100% of the 24-h posttransfusion increment >20% difference in 24-h recovery between S-303 treated and non-s-303 treated RBC from the implicated donor by biotin labeling challenge (if available) 27

28 Stopping Rules - 1 " The study will be stopped if two subjects demonstrate a confirmed antibody with specificity to S 303 treated RBC and experience a clinically significant hemolytic transfusion reaction with accelerated RBC clearance (HTR) (defined in Protocol Section 8.4). 28

29 Stopping Rules - 2 " If three subjects demonstrate a confirmed positive test for antibody with specificity to S 303 treated RBC, but in the absence of clinical evidence of accelerated RBC clearance, the study will be paused for investigation of the antibody characteristics and assessment of clinical significance (Section and 8.4.2). 29

30 Data and Safety Monitoring Board " A Cohen - thalassemia (Philadelphia) " L Pierelli transfusion medicine (Rome) " T Peyrard - immunohematology (Paris) 30

31 Proposed U.S. Phase III chronic RBC transfusion Group A Efficacy & Safety Assessment (n=82, cross-over) 1 efficacy endpoint = Hemoglobin usage Screen, randomize n=41 n=41 n=218 INTERCEPT 2 txns* 6 txns 2 txns* Control 6 txns INTERCEPT Control 2 txns* 6 txns 2 txns* 6 txns INTERCEPT Group B Safety Assessment Only (n=291, 3:1 ratio) Screen, randomize n=73 3 txns 3 txns Control Safety Assessment: Groups A & B (n=373) 1 safety endpoint = % patients with S-303 Abs with clinically significant hemolysis * Group A patients receive 2 wash-in transfusions followed by 6 transfusions evaluated for efficacy.

32 New RBC Biologic Component Enabling Safer Chronic Tx? Pathogen inacjvated WBC inacjvated (without gamma damage) Phenotyped/genotyped Very low plasma content Defined hemoglobin (gms) Defined Fe (mg) Diminished HLA and/or RBC alloimmunizajon potenjal? BE SURE.

33 Summary " SCD and thalassemia pajents living longer and needing more transfusion " Chronic transfusion pajents very highly exposed to known and unknown transfusion risks " Pathogen inacjvated RBC limit transfusion risk: Known and emerging pathogens (very broad spectrum) InacJvate WBC Very low plasma content (allergic reacjons, TRALI etc) Studies of alloimmunizajon needed " US & EU chronic studies among the largest undertaken: Rigorous assessment of RBC efficacy Very large safety data base " Technology could be adaptable to the problem of blood safety in the developing world. BE SURE.