# Presentation: 730811

## C1 Esterase Inhibitor (Human) (CinryzeTM)Lev Pharmaceuticals, Inc.

- Felice D’Agnillo, PhDDivision of HematologyOBRR/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

## C1 Esterase InhibitorTarget Pathways

- C1 complex(C1s, C1r)

- C4b, C2a

- C1INH

- ClassicalComplementpathway

- Kallikrein, FXIIa, FXIa

- Bradykinin, thrombin

- Coagulation and Kinin pathways

- Plasmin, tPA

- Fibrin degradation

- Fibrinolyticpathway

## 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%)

## HAE Classification

| Condition | C1q | C1s | C1-INH
antigenic | C1-INH function | C4 | C3 |
| --- | --- | --- | --- | --- | --- | --- |
| HAE-I | N | N | <30% | <30% | L | N |
| HAE-II | N | N | N/H | <30% | L | N |
| Estrogen-dependent inherited angioedema | N | N | N | N | N | N |
| Acquired C1-INH deficiency type I | <30% | <30% | <50% | L | <30% | N/L |
| Acquired C1-INH deficiency type II | L/(N) | L | N/L | L | <30% | N/L |

- 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: CinryzeTM
- 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

- 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

- CinryzeTM Manufacturing

## CinryzeTM Viral Inactivation/RemovalFDA analysis of Sponsor’s data

- CinryzeTM Viral Inactivation/RemovalFDA analysis of Sponsor’s data

## 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