C1 Esterase Inhibitor Human Cinryze Lev Pharmaceuticals, Inc'

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

• Felice DAgnillo, PhDDivision of
  HematologyOBRR/CBER/FDA

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Outline

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

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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)
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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
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Hereditary Angioedema

• Autosomal-dominant disease
• Incidence 110,000 to 150,000 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)

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HAE Classification
H, High L, low N, normal
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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.

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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)

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Cinryze Manufacturing

• US-licensed Source Plasma
• Two dedicated, independent and effective viral
  reduction steps
• heat treatment at 60C 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

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Cinryze Viral Inactivation/RemovalFDA analysis
of Sponsors data
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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