C1 Esterase Inhibitor (Human) (Cinryze™) Lev Pharmaceuticals, Inc. Felice D’Agnillo, PhD Division of Hematology OBRR/CBER/FDA

Outline INTRODUCTION AND BACKGROUND PRODUCT INFORMATION REGULATORY CHRONOLOGY CLINICAL OVERVIEW EFFICACY – PIVOTAL STUDIES SAFETY IMMUNOGENICITY

C1 Esterase Inhibitor Bos I.G.A et al, Immunobiology (2002) Serine protease inhibitor (i.e. Serpin) Plasma concentration (~180  g/ml) 478 aa, 105 kD (SDS-PAGE) ~30-50% glycosylated Serpin domain contains a reactive site loop (RSL), 3  -sheets, and 9  - helices Reactive site loop Arg444 (P1)

C1 Esterase Inhibitor Target Pathways C1 complex (C1s, C1r) C4b, C2a C1INH Classical Complement pathway Kallikrein, FXIIa, FXIa Bradykinin, thrombin Coagulation and Kinin pathways Plasmin, tPA Fibrin degradation Fibrinolytic pathway

Hereditary Angioedema Autosomal-dominant disease Incidence: 1:10,000 to 1:50,000 worldwide, ~10,000 in U.S. Attacks –spontaneous, stress, trauma, injury, or surgery –swelling of the face, airway, extremities, and digestive tract –episodic, self-limited –occasionally life-threatening –duration-hours to days C1INH deficiency (Type I, 85%) or dysfunctional (Type II, 15%)

ConditionC1qC1s C1-INH antigenic C1-INH function C4C3 HAE-INN<30% LN HAE-IINNN/H<30%LN Estrogen-dependent inherited angioedema NNNNNN Acquired C1-INH deficiency type I <30% <50%L<30%N/L Acquired C1-INH deficiency type II L/(N)LN/LL<30%N/L HAE Classification H, High; L, low; N, normal

Management of HAE Avoidance of known triggers –Estrogens –ACE inhibitors Therapeutic Interventions –Anti-fibrinolytic agents (e.g., tranexamic acid) have been used in Europe –Attenuated androgens for increasing C1INH levels (prophylaxis) –FFP replacement (risk/benefit sometimes questioned) –C1INH concentrates in Europe –C1INH concentrates under IND in U.S.

C1 Esterase Inhibitor (Human) Product Information Trade name: Cinryze™ Sterile, stable, lyophilized preparation of highly purified C1 inhibitor derived from human plasma Manufactured under contract to Sanquin Blood Supply Foundation (The Netherlands)

US-licensed Source Plasma Two dedicated, independent and effective viral reduction steps –heat treatment at 60°C for 10 hours in an aqueous solution with stabilizers, and –nanofiltration through two sequential 15 nm Planova filters Additionally, PEG precipitation has been shown to remove viruses Cinryze™ Manufacturing

Cinryze™ Viral Inactivation/Removal FDA analysis of Sponsor’s data VirusPEG Precipitation Heat Treatment NanofiltrationTotal Log Reduction HIV-15.1 ≥ 6.1 ≥ 5.6 ≥ 16.8 PRV ≥ 6.0 ≥ 6.7 ≥ 6.4 ≥ 19.1 BVDV4.5 ≥ 6.7 ≥ 5.5 ≥ 16.7 HAV2.8 ≥ 4.9 > 10.5 CPV

Questions to the Committee Question #1 Is the safety and efficacy evidence sufficient for approval of Cinryze TM for prophylactic treatment of HAE? Question #2 If the answer to Question #1 is yes, should post-marketing studies be performed to further evaluate the following: the optimal dose for prophylaxis in males and females immunogenicity long-term safety