Imaging of white blood cells with Scintimun APRAMEN Réunion, Mardi 8 février 2011, Paris Wolf S. Richter
SCINTIMUN : IgG1 antibody targeting white blood cells Tc-99m kit; murine IgG1 antibody target: NCA-95 on granulocytes (located in cytoplasm and on cell membrane) in vitro selectivity: reacts with more than 90% of granulocytes in peripheral blood and precursors of granulocytes in the red bone marrow; reaction with monocytes is less than 5% Page 2 does not impair granulocyte function allows scintigraphic imaging of granulocytes accumulation (infection/inflammation)
Page 3 Tc-99m WBC Scintimun 4 hrs p.i. Images: courtesy of Prof Meller, Goettingen, Germany
SCINTIMUN : A long history 2010 Approval in Europe (centralized procedure) 2010 since 1992, used in several European countries - partly on the basis of individual prescription (total of ~100,000 patients) Pivotal trial: AG-PH3 (9/06 1/08) 2005 MR procedure for European registration (2004) 2000 1995 1990 Page 4 marketing authorization in Switzerland, Sweden, Hungary, and Czech Republik between 1992 and 1994 Clinical Development Behring Werke AG
2004/5: EMEA requested an additional phase III study Design questions: Indication: osteomyelitis most relevant fever of unknown origin infection / inflammation of vascular grafts Page 5 Comparator: Efficacy: labeled white blood cells Leukoscan immunology other imaging methods (MRI, CT, x-ray) FDG-PET not appropriate not sufficiently available sensitivity / specificity vs histology sensitivity / specificity vs investigator diagnosis sensitivity / specificity vs truth panel agreement between SCINTIMUN and WBC not easily feasible secondary requested by EMEA primary
Phase 3 study: AG-PH3 119 patients (per protocol), 27 study centers in Europe; intra-individual individual comparison against 99m Tc labeled white blood cells Scintimun WBC screening WBC Scintimun 1 mo follow-up Page 6 Evaluation: blinded image evaluation (blind read, 3 nuclear physicians), truth panel assessment (1 nuclear physician, 1 radiologist, 1 orthopedist) Patients suspected or documented osteomyelitis (acute, subacute, chronic) patients with loosening of joint prosthesis patients with diabetic foot Primary objective: agreement rate of SCINTIMUN with 99m Tc-WBCs Secondary objectives: image quality, safety (HAMA )
Case 1: concordance infection 4 h SCINTIMUN 24 h Page 7 WBC 4 h 24 h ROIs drawn by blinded reader
Case 2: higher image quality and additional lesion SCINTIMUN 4 h SCINTIMUN 24 h Page 8 WBC 4 h 24 h ROIs drawn by blinded reader
AG-PH3: SCINTIMUN and WBC provide comparable information Page 9 Agreement Standard Lower limit of rate error the 95% CI* Reader 1 0.81 0.02 0.76 Reader 2 0.84 0.02 0.79 Reader 2 0.85 0.02 0.80 across all 3 readers 0.83 0.01 0.80 * CI: confidence interval Expected agreement for 2 (independent) tracers with 90% accuracy each: 0.9 x 0.9 + 0.1 x 0.1 = 82%
Sensitivity and Specificity (Dx at 1 month as gold standard) [%] 80 70 60 50 40 30 20 10 0 Se Sp Scintimun WBC Scintimun detects more patients with osteomyelitis (higher sensitivity); however, also more false positives (lower specificity) Page 10 SCINTIMUN Tc 99m WBCs Sensitivity [95% CI] Sensitivity [95% CI] Reader 1 0.770 [0.674; 0.867] 0.703 [0.598; 0.808] Reader 2 0.757 [0.658; 0.855] 0.514 [0.399; 0.628] Reader 3 0.716 [0.613; 0.820] 0.554 [0.440; 0.668] Across readers 0.748 [0.666; 0.829] 0.590 [0.497; 0.683] Specificity [95% CI] Specificity [95% CI] Reader 1 0.641 [0.575; 0.861] 0.667 [0.517; 0.817] Reader 2 0.795 [0.667; 0.923] 0.897 [0.801; 0.994] Reader 3 0.718 [0.575; 0.861] 0.821 [0.699; 0.943] Across readers 0.718 [0.594; 0.842] 0.795 [0.703; 0.887] patient-based analysis
SCINTIMUN has advantages in CHRONIC osteomyelitis chronic [%] [%] acute 80 70 60 50 40 30 20 10 0 Se Sp Scintimun WBC 100 80 60 40 20 0 Se Sp Scintimun WBC Page 11 no. SCINTIMUN Tc 99m WBCs SENSITIVITY chronic 60 0.733 0.544 (p<0.05) acute 13 0.846 0.821 SPECIFICTY chronic 28 0.726 0.774 (n.s.) acute 11 0.697 0.848
A step aside: The effect of blind reading Example Myocardial scintigraphy Page 12
A step aside: The effect of blind reading Example Myocardial scintigraphy Page 13
SCINTIMUN :AG-PH3 compared to published results Sensitivity Specificity it SCINTIMUN meta-analysis 88.9% 81.4% (15 studies, blind read mentioned in 10; 523 data points) AG-PH3 74.8% 71.8% Page 14 Tc-99m WBCs meta-analysis 90.7% 91.4% (11 studies, blind read mentioned in 2; 922 data points) AG-PH3 59.0% 79.5%
AG-PH3: SCINTIMUN provides higher image quality Patients with good or excellent image quality[%] 80 70 60 50 40 30 20 10 0 Scintimun WBC Scintimun provides higher image quality Page 15 Image quality SCINTIMUN Tc 99m WBCs Excellent 40 (11%) 13 (4%) Good 227 (64%) 186 (52%) Moderate 71 (20%) 110 (31%) Poor 13 (4%) 41 (11%) Not evaluable 6 (2%) 7 (2%) Total no. of assessments 357 (100%)* 357 (100%) * total number of assessments is 357: 119 patients assessed by 3 readers
Safety - HAMA HAMA (human anti-mouse antibodies) determined d in all clinical i l studies Page 16 tested with anti-idiotype kit Study BI 71.015: sign. increase in 6 of 162 patients (3.7%) Study 7D-101 SZ-A: elevated HAMA in 1 of 24 patients (4.2%) Study 7D-201 SZ-A: elevated HAMA in 1 of 31 patients (3.2%) Study 7MN-301 SZ-A: 20 patients t HAMA positive; incidence id of HAMA increased from 1.3% (day 14) to 4.1% (day 30) Study 7MN-302 SZ-A: measurements not available Study 306340: none of the patients studied with the product manufactured according to the new process showed an increase in HAMA tested t with anti-isotype i t kit: Study AG-PH3: HAMA in 16 of 116 patients after SCINTIMUN (13.8%)
Safety Favorable Safety Profile in Separate Survey non-interventional ti safety study in 2,078 patients t 1,112 patients received SCINTIMUN 996 patients received another radiopharmaceutical (mostly 111 In-WBC and 67 Ga) SCINTIMUN 61 AEs in 31 patients (8.3%) 5 SAEs (all not related to SCINTIMUN) Page 17 other radiopharmaceutical 171 AEs in 119 patients (12.3%) 1 SAE (not related to other radiopharmaceutical )
SCINTIMUN (approved SmPC) Indications SCINTIMUN is indicated for scintigraphic imaging: in conjunction with other appropriate imaging modalities, for determining the location of inflammation/infection in peripheral bone in adults with suspected osteomyelitis SCINTIMUN should not be used for the diagnosis of diabetic foot infection Page 18 Acquisition of images starts 3 to 6 h after administration and may be followed by late images 24 hours after initial injection Acquisition: planar imaging or SPECT (SPECT/CT) Contraindications Hypersensitivity to the active substance, to other murine antibodies, or to any of the excipients Positive screening test for human anti-mouse antibody (HAMA) Pregnancy
SCINTIMUN : Characteristics of Images (clinical experience) Page 19 Accumulation in infection / inflammation Accumulation in bone marrow (spine, proximal parts of peripheral skeleton, pelvis) difference to labeled WBCs may lead to misinterpretations; solution for most cases: SPECT/CT Increase of specific uptake at sites of infection between 4 and 24 hrs simultaneous analysis of images from early and late imaging to increase diagnostic confidence a significant increase from 4 to 24 hours has been regarded as a sign of infection (used for differentiation vs sterile inflammation) radioactivity excretion via abdomen and urinary bladder limited accuracy in the abdomen
SPECT / CT helps in the differential diagnosis female, 61 yrs, pain a.s., infection left tibial prothesis, aspiration: Lactobacillus gasseri,crp-increase Diagn.: Infection Page 20 Diagn.: Infection Diagn.: Infection SPECT/CT: Clear allocation to prosthesis and extent of infection Images: courtesy of Prof Hacker, Munich, Germany
Infection: Increase in Uptake between 4 and 24 hours 60 year-old patient TEP left hip in 1988, revisions in 2002 and 2008 suspicion i of osteomyelitis antibiotic treatment successfully stopped the inflammatory process^^ 4hrs Page 21 24 hrs
Microbiological cultures were obtained in 17 patients Sensitivity [%] 100 Scintimun had higher sensitivity 80 than Tc-99m WBC in patients with confirmed infection 60 40 20 0 Scintimun WBC Page 22 SCINTIMUN 99mTc WBCs Reader 1 6 TP, 1 FN 4 TP, 3 FN Reader 2 6 TP, 1 FN 4 TP, 3 FN Reader 3 6 TP, 1 FN 5 TP, 2 FN total 18 TP, 3 FN Sensitivity: 85.7% TP: true positive; FN: false negative 13 TP, 8 FN Sensitivity: 61.9%
SCINTIMUN and WBC show comparable performance for differentiation between infection and sterile inflammation assessment of the local l investigator t (1 months follow-up): 34 patients with infection 31 patients with sterile inflammation Page 23 Sensitivity Specificity Accuracy SCINTIMUN 47% 77% 62% WBC 44% 87% 65% n.s.
Literature Review Page 24 Studies Patients Bone marrow imaging 20 643 Osteomyelitis 12 483 Inflammtory bowel disease, Appendicitis 11 302 Inflammation: mixed indications (incl. osteomyelitis) 5 277 Endocarditis diti 4 137 Fever of unknown origin 3 115 Pharmacokinetics 3 64 Pancreatitis 1 63 Diabetic foot 1 25... 15 357 Σ 75 2,466
off label use: metastasis imaging metastases in the spine are characterized by a photopenic defect Page 25
off label use: Infection of Vascular Grafts before antibiotic tx Page 26 after antibiotic tx
Scintimun is efficacious in Fever of Unknown Origin (off label use) Sponsored Studies: Pilot Study: Sensitivity 23%, Specificity 100% (n=45) Phase III: Sensitivity 63%, Specificity 95% (n=71) Becker et al., 1993 34 consecutive patients with FUO Sensitivity: 40%, Specificity: 92% (low Spec. explained by high number of FN findings in endocarditis, pneumonia, small brain abscesses) Page 27 Meller et al., 1998 51 FUO patients Sensitivity for pyogenic foci: 73%, Specificity: 97% Gratz et al., 1998 30 neonates and infants with FUO Sensitivity: 72%, Specificity: 95% (all FN findings in spondylitis)
Conclusions SCINTIMUN has been successfully and safely used in more than 100,000000 patients SCINTIMUN provides comparable diagnostic accuracy than WBC in osteomyelitis SCINTIMUN is easy to use (kit) up to 4 patients can be studied with 1 vial significantly reducing cost and preparation time Page 28 bone scan SCINTIMUN