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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

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c1 esterase inhibitor human cinryze lev pharmaceuticals inc

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

Felice D’Agnillo, PhDDivision of HematologyOBRR/CBER/FDA

outline
Outline
  • INTRODUCTION AND BACKGROUND
  • PRODUCT INFORMATION
  • REGULATORY CHRONOLOGY
  • CLINICAL OVERVIEW
  • EFFICACY – PIVOTAL STUDIES
  • SAFETY
  • IMMUNOGENICITY
slide3

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)

c1 esterase inhibitor target pathways
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

hereditary angioedema
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%)
slide6

HAE Classification

H, High; L, low; N, normal

management of hae
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
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)
slide9

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
slide10

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

questions to the committee
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