6
List of Figures
Figure 1 CSL Behring’s Production Facility in Marburg, Germany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 2 Emil von Behring, Recipient of the Nobel Prize. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 3 Key Achievements and Milestones for CSL Behring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 4 Hereditary Angioedema is an Autosomal Dominant Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 5 Pathophysiology of Hereditary Angioedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 6 C1-INH Acts as a Downregulator in 4 Enzyme Cascades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 7 Age at Onset of Clinical Symptoms in 221 Patients With Hereditary Angioedema . . . . . . . . . . . . . . 18
Figure 8 Common Sites of Attacks in Hereditary Angioedema. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 9 Computed Tomograms of the Abdomen, Showing Perihepatic Effusion (Top) and
Intestinal Wall Edema (Bottom) During an Attack of Angioedema in the Gastrointestinal Tract. . . . . 20
Figure 10 Frequency of Angioedema Attacks in 1,168 Patients During 1 Year . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 11 Erythema Marginatum in Hereditary Angioedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Figure 12 Diagnostic Algorithm for HAE-I and HAE-II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Figure 13
Ask 8 to Differentiate
Diagnostic Tool . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Figure 14 Phase III Prospective, Multinational, Randomized, Parallel-group, Placebo-controlled,
Dose-finding, Double-blind I.M.P.A.C.T.1 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Figure 15 Kaplan-Meier Curve for Time to Onset of Symptom Relief, as Determined
by Patients’ Assessment in I.M.P.A.C.T.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Figure 16 Median Time to Onset of Symptom Relief by Severity of Attack
(Berinert
®
20 IU/kg Body Weight vs Placebo) in I.M.P.A.C.T.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Figure 17 Median Time to Complete Resolution of Symptoms
(Berinert
®
20 IU/kg Body Weight vs Placebo) in I.M.P.A.C.T.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Figure 18 Patient-reported Time to Onset of Symptom Relief by Site of HAE Attack
(Berinert
®
20 IU/kg Body Weight) – Per-patient and Per-attack Analysis . . . . . . . . . . . . . . . . . . . . . . 39
Figure 19 Patient-reported Time to Complete Resolution by Site of HAE Attack
(Berinert
®
20 IU/kg Body Weight) – Per-patient and Per-attack Analysis . . . . . . . . . . . . . . . . . . . . . . 39
Figure 20 Median and 95% Confidence Intervals of Times to Onset of Symptom Relief
and Complete Resolution of HAE Symptoms by Subgroups – Per-patient Analysis . . . . . . . . . . . . . . 40
Figure 21 Time Between Consecutive HAE Attacks Treated With Berinert
®
in Patients
Treated for
≥
15 Attacks (n=18) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Figure 22 18-Year-old Patient Before (Left) and After (Right) Treatment With Berinert
®
. . . . . . . . . . . . . . . . . . 41
Figure 23 Berinert
®
Comes With a Complete Administration Set . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Figure 24 Mix2Vial
™
Transfer System Simplifies the Administration Process of Berinert
®
and Eliminates the Risk of Needlestick Injury During Reconstitution . . . . . . . . . . . . . . . . . . . . . . . . . 47
Figure 25 Structure of Berinert
®
(C1-INH) Molecule. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Figure 26 Berinert
®
Mechanism of Action as a Serpin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Figure 27 Decrease of Plasma Bradykinin Concentration After Infusion of C1-INH Concentrate
During an HAE Attack . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Figure 28 Simplified Diagram of Inhibition of the Interrelated Serine Protease Cascades of the
Complement, Kallikrein-Kinin, Coagulation, and Fibrinolytic Systems. . . . . . . . . . . . . . . . . . . . . . . . 55
Figure 29 Simplified Flow Diagram of the Manufacture of Berinert
®
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Figure 30 Protein Gel Electrophoresis (8% to 16% Tris Glycine; 5 mOD/lane) . . . . . . . . . . . . . . . . . . . . . . . . . 59
Figure 31 CSL Behring’s Integrated Safety System for Plasma Derivatives From Donation
to the Finished Commercial Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
