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

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Presentation on theme: "C1 Esterase Inhibitor (Human) (Cinryze™) Lev Pharmaceuticals, Inc. Felice D’Agnillo, PhD Division of Hematology OBRR/CBER/FDA."— Presentation transcript:

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

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

3 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)

4 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

5 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%)

6 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

7 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.

8 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)

9 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

10 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

11 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


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