1 / 11

C1 Esterase Inhibitor (Human) (Cinryze™) Lev Pharmaceuticals, Inc.

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

norman
Download Presentation

C1 Esterase Inhibitor (Human) (Cinryze™) Lev Pharmaceuticals, Inc.

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. C1 Esterase Inhibitor (Human) (Cinryze™)Lev Pharmaceuticals, Inc. Felice D’Agnillo, PhDDivision of HematologyOBRR/CBER/FDA

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

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

  4. C1 Esterase InhibitorTarget Pathways C1INH C1 complex(C1s, C1r) ClassicalComplementpathway C4b, C2a Coagulation and Kinin pathways Kallikrein, FXIIa, FXIa Bradykinin, thrombin Fibrin degradation Fibrinolyticpathway Plasmin, tPA

  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. 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. Cinryze™ Manufacturing • 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

  10. Virus PEG Precipitation Heat Treatment Nanofiltration Total Log Reduction HIV-1 5.1 ≥ 6.1 ≥ 5.6 ≥ 16.8 PRV ≥ 6.0 ≥ 6.7 ≥ 6.4 ≥ 19.1 BVDV 4.5 ≥ 6.7 ≥ 5.5 ≥ 16.7 HAV 2.8 2.8 > 10.5 ≥ 4.9 8.7 CPV 4.2 4.5 Cinryze™ Viral Inactivation/RemovalFDA analysis of Sponsor’s data

  11. Questions to the Committee Question #1 Is the safety and efficacy evidence sufficient for approval of CinryzeTM 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

More Related