FDA Briefing Document
Blood Products Advisory Committee Meeting
CinryzeTM (C1-esterase
Inhibitor (Human) Nanofiltered (C1INH-nf)
Lev Pharmaceuticals, Inc.
Basil Golding, MD
Division of Hematology
OBRR/CBER/FDA
TABLE OF CONTENTS
PAGE
1.0 GENERAL INFORMATION 3
PRODUCT
NAME
PRODUCT
COMPOSITION
PROPOSED
INDICATION
PROPOSED
AGE GROUP
DOSING
REGIMEN AND ROUTE OF ADMINISTRATION
EXECUTIVE
SUMMARY 5
2.0 INTRODUCTION AND BACKGROUND 7
2.1 REGULATORY BACKGROUND 9
2.3 BASIS FOR LICENSURE 10
3.0 CLINICAL
OVERVIEW 13
3.1 EFFICACY – PIVOTAL STUDIES
17
3.2 IMMUNOGENICITY
24
3.3 SAFETY 25
3.4 STATISTICAL REVIEW 28
APPENDIX 1 Adverse Events in prior studies 32
APPENDIX 2 Adverse Events in 2005-1 Part A 34
APPENDIX 3 Adverse Events in 2005-1 Part B 35
APPENDIX 4 Viral Inactivation/Removal 39
1.0
GENERAL INFORMATION
Product name
Established
name: C1-esterase Inhibitor (Human)
Nanofiltered (C1INH-nf)
Proposed trade name: CinryzeTM
Product composition (from the
Applicant’s proposed label):
CinryzeTM is a sterile, stable, lyophilized preparation of highly
purified C1 inhibitor derived from human plasma. Cinryze
is manufactured from human plasma purified by a combination of filtration and
chromatographic procedures. The specific activity of Cinryze is ≥ 4.0 U/mg. The purity is
≥
90% human C1 inhibitor. Following reconstitution with 5 mL of Sterile Water for
Injection, USP, each vial contains approximately 500 U of functionally active
C1 inhibitor. It has a pH
between 6.6 and 7.4 and an osmolality between 200
- 400 mosmol/kg. One Unit (U) of Cinryze
corresponds to the mean quantity of C1
inhibitor present in 1 mL of normal fresh plasma.
The
manufacturing process for Cinryze includes processing steps
designed to reduce the risk of viral transmission. Screening against
potentially infectious agents begins with the donor selection process and
continues throughout plasma collection and plasma preparation. Each individual
source plasma donation used in the manufacture of Cinryze is collected only at FDA-approved blood establishments and
is tested by FDA licensed serological tests for Hepatitis B Surface Antigen
(HBsAg), and for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and
Hepatitis C Virus (HCV). Additionally, all plasma used in the manufacture of
this product was tested by FDA-licensed Nucleic Acid Tests (NAT) for HCV and
HIV-1 and found to be non-reactive (negative).
Two dedicated, independent and effective viral reduction
steps are employed in the manufacture of Cinryze: heat
treatment at 60°C for 10 hours in an aqueous solution with stabilizers, and
nanofiltration through two sequential 15 nm Planova filters. These viral
reduction steps, along with a step in the manufacturing process, PEG
precipitation, have been validated in a series of in vitro experiments for their capacity to inactivate/remove a wide
range of viruses of diverse physicochemical characteristics including: Human
Immunodeficiency Virus (HIV), Hepatitis A Virus (HAV), and the following model
viruses: Bovine Viral Diarrhea Virus (BVDV) as a model virus for HCV, Canine
Parvovirus (CPV) as a model virus for Parvovirus B19, and Pseudorabies Virus
(PRV) as a model virus for Hepatitis B Virus (HBV).
Manufacturer: Lev Pharmaceuticals under contract to Sanquin Blood Supply
Foundation (The Netherlands)
Proposed
indication: C1 Inhibitor replacement therapy for use in patients with
Hereditary Angioedema (HAE) to prevent attacks.
Dosing regimen: A dose of 1000 U Cinryze is
recommended to be administered twice weekly for long term preventive replacement
therapy of C1 inhibitor in HAE patients.
Route of administration: Intravenous
Potency: Approximately
500 U/vial. Two vials are combined to make a single dose. Each single-use vial
contains the following excipients: 4.1 mg/mL sodium chloride, 21 mg/mL sucrose,
2.6 mg/mL trisodium citrate, 2.0 mg/mL L-Valine, 1.2 mg/mL L-Alanine, 4.5 mg/mL
L-Threonine when reconstituted with the appropriate amount of diluent
EXECUTIVE SUMMARY
This briefing document contains a
summary of efficacy and safety data provided by Lev Pharmaceuticals, Inc. to support approval of CinryzeTM, C1-esterase Inhibitor (Human) Nanofiltered (C1INH-nf) indicated for the prevention of
hereditary angioedema attacks. CinryzeTM
is to be administered twice weekly to pediatric or adult hereditary angioedema
patients. The proposed release specification potency is 500 U/vial, with a shelf-life of 2 years when stored at
2°C–25°C (36°F-77°F).
The Biologics Licensing
Application (BLA) contains the following two adequate and well-controlled
1) LEVP 2006-5 [phase 1 for
pharmacokinetics and safety] and
2) LEVP 2005-1 [phase 3, Part A:
treatment of HAE attacks, Part B: prophylaxis of HAE attacks].
This briefing document will only discuss LEVP 2005-1 Part B
(prophylaxis of HAE attacks). LEVP 2005-1 Part A (treatment of HAE attacks)
is still under review by FDA.
The
BLA also contains summary reports for the following uncontrolled studies:
LEVP
2006-1
Design: open
label extension protocol for treatment of HAE attacks for subjects who
completed LEVP 2005-1/Part A & LEVP 2005-1/Part B
LEVP
2006-4
Design: open
label extension protocol for prophylaxis of HAE attacks for subjects who
completed LEVP 2005-1/Part A & LEVP 2005-1/Part B
Clinical
Trials using C1-esteraseremmer-HP (CETOR®)(an earlier European
version of the product):
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KB2003.01
Design: Part
A – phase 1 cross-over PK and safety study comparing C1-esteraseremmer-HP
(CETOR®)
Efficacy
Efficacy was evaluated in study
2005-1 Part A for treatment of hereditary angioedema (HAE) attacks, and in
2005-1 Part B for prophylaxis of HAE attacks.
Part A (treatment of HAE attacks)
is still under review by FDA and will not be discussed at this Advisory
Committee.
Part B (prophylaxis of HAE
attacks) demonstrated efficacy in reducing the frequency of HAE attacks to
varying extents in a randomized, blinded prophylaxis study comparing CinryzeTM to placebo. In a pre-specified Analysis of Variance (ANOVA), with
each individual serving as his/her control, the reduction in frequency of
attacks per unit time comparing the treatment and placebo periods was highly
significant (p < 0.0001). Upon review of individual subject response data,
there was an aggregate 50% reduction in the frequency of HAE attacks during a
90 day active prophylaxis period compared to a 90 day placebo prophylaxis
period. Although most individuals
experienced some decrease in frequency of attacks, individual responses to CinryzeTM
prophylaxis were variable and ranged from a 100% reduction in the
frequency of HAE attacks to an 85% increase in the frequency of HAE attacks in
one subject.
No dose finding studies were
conducted to support the recommended dose schedule for prophylaxis, which was
1000 units intravenous, 2 or 3 times per week. Dosing was based on published
reports of the clinical use of C1 esterase inhibitor replacement therapy. FDA proposes the performance of postmarketing
studies to evaluate dosing regimens.
Immunogenicity
Immunogenicity to CinryzeTM was assessed by measuring serum anti-C1INH antibodies at
baseline and at various times after dosing for Part A and Part B. The first central
laboratory reported many samples as positive. However, repeat testing
of samples at the same laboratory produced inconsistent results. Two
subsequent laboratories tested subsets of the samples and reported them as
negative. There was
no definite evidence linking the putative antibodies determined in the first
laboratory, with adverse events or reduced efficacy of CinryzeTM. FDA
proposes postmarketing studies to evaluate
this issue further.
Safety
The safety profile of CinryzeTM when used for prophylaxis at the recommended dose schedule
appears to be acceptable. Adverse events
that were noted were likely due to intercurrent illnesses and the underlying
disease rather than due to CinryzeTM. There were no deaths and no adverse events
that led to study discontinuation. There
were 4 subjects with treatment-emergent serious adverse events (laryngeal
edema, resolved; lymphadenopathy, resolved; severe hereditary angioedema,
resolved with sequelae; and moderate hereditary angioedema, resolved). FDA proposes post marketing safety monitoring
to evaluate the effects of repeated and long-term treatment.
Conclusion
CinryzeTM at a potency of 1000 U i.v. two to three times per week was effective in reducing
the frequency of hereditary angioedema attacks in subjects with hereditary
angioedema. The safety profile of this prophylactic dose schedule of CinryzeTM
appears to be acceptable. The
immunogenicity of CinryzeTM at this dose schedule remains to be
evaluated.
2.0
INTRODUCTION AND
BACKGROUND
C1 Esterase Inhibitor (C1INH) is
a 104 kD plasma glycoprotein (35% carbohydrate) that was first described in the
late 1950’s as the plasma activity that inhibits the C1 proteinase activity of
the complement cascade. It appears to be
the only inhibitor of C1 esterase. Subsequent research demonstrated that it is
a more general proteinase inhibitor of the serpin class, having inhibitory
activity against C1r, C1s, kallikrein and Factor XIIa. In
vitro, it inhibits plasmin. However,
it does not appear to be a significant inhibitor of plasmin in vivo.
C1 esterase
inhibitor has the following activities, as shown in the following diagram:
·
inhibition of the classical complement cascade,
·
inhibition of coagulation
factors XIa and XIIa
·
inhibit of the
conversion of plasminogen to plasmin
·
inhibition of
activated kallikrein in the kallikrein-bradykinin pathway.

From J Am Acad Dermatol
53(3):373-88
(2005)
Upper figure: diagrammatic
representation of plasma kinin-forming cascade indicating steps inhibitable by
C1INH. All functions of factor XIIa and kallikrein are affected. Lower figure:
further digestion of factor XIIa by kallikrein and plasmin generates factor XII
fragment (XIIf), which initiates the complement cascade. Both factor XIIf and
C1 are inhibited by C1INH.
Hereditary Angioedema.
From A.L. Sheffer, M.D., J Allergy Clin Immunol 120:756-757 (2007):
Hereditary angioedema (HAE) is an autosomal-dominant
condition [chromosome 11], characterized by episodic self-limited, occasionally
life-threatening attacks of angioedema. Affected
individuals lack sufficient functional inhibition of the first complement
protein, the serine proteinase inhibitor C1INH. In
most instances, the C1INH is absent (type I), but 15% of affected individuals may
possess a nonfunctional C1INH (type II). These
2 types of HAE cannot be distinguished clinically. The incidence varies from
1:10,000 to 1:50,000 persons. The biological role of the C1INH is to regulate
the intrinsic and contact coagulation pathways as well as the complement
system. In the former, plasma kallikrein and coagulation factors
XIa and XIIa (Hageman factor) are inhibited, and in the latter, C1r and C1s are
inhibited. When C1INH is deficient or absent, bradykinin is released from the
high-molecular weight kininogen by plasma kallikrein in abnormally high
amounts. Experiments with C1INH knockout mice have confirmed
that increased vascular permeability in HAE is mediated by bradykinin via the
contact system.
2.1
REGULATORY BACKGROUND
There are no
The following summarizes the regulatory chronology
of this BLA:
14-Aug-2007 Review Committee formed
2.2
BASIS FOR LICENSURE
The applicant conducted a phase 3 study 2005-1 composed of two parts, 1)
Part A for treatment of HAE attacks in 71 subjects with hereditary angioedema,
and 2) Part B for prophylaxis of HAE attacks in 22 subjects who had completed
participation in Part A.
In
addition, the applicant conducted a randomized, parallel group open label
pharmacokinetics study 2006-5 in subjects with hereditary angioedema.
2005-1
Part A (treatment of HAE attacks) is still under FDA review, and will not be
discussed before this Advisory Committee.
2005-1 Part B (prophylaxis of HAE attacks) demonstrated safety and efficacy for the prophylaxis indication, and is discussed below.
2.21 Brief Synopsis of Study Procedures for Part
A
and
for Part B
Enrolled subjects who completed Part A
(treatment of acute attacks), and who demonstrated a high frequency of HAE
attacks (2 or more per month) were randomized to 12 wks prophylaxis with either
C1INH or placebo (infused at study site), followed by a cross-over to 12 wks
prophylaxis with the other study agent.
HAE attacks of any severity were recorded. Subjects in either arm
received open label C1INH, 1000 U, if treated during acute attacks while on the
prophylaxis part of the study. Since enrollment in the prophylaxis study (Part
B) depended on participation in Part A (treatment of acute attacks), the study
procedures for Part A are described below:
a.
Subjects
are screened to confirm the diagnosis of HAE and to establish a baseline C4
level.
b.
Subjects
who meet the eligibility criteria are enrolled and wait for the first HAE
attack meeting the treatment eligibility criteria.
c.
When an
eligible HAE attack occurs, the subject travels to the treatment site and must
be treated within 4 hour of the attack onset to remain eligible. There were 71 subjects with an eligible HAE
attack that was treated.
d.
Subjects
designate a “defining symptom” from among the following 3 categories: facial,
gastrointestinal, or genitourinary and a serum C4 level is measured for
comparison with the serum C4 level at screening.
e.
Subjects
are monitored every 15 minutes for 8.5 hours to record response data.
f.
Treated
subjects are retrospectively entered into the data analysis set if the serum C4
level at treatment start is lower than the serum C4 level at screening, thereby
confirming the presence of an HAE attack. Anomalous serum C4 results (HAE
subjects should have normal C4 levels at baseline with a decreased level at the
time of an attack) caused the sponsor to use a “judiciary” to examine the data
for 23 of 71 subjects to decide whether they should be included in the data
analysis set. The judiciary ruled that
20 of the 23 subjects should be included.
g.
Due to some
subjects exhibiting low C1q levels, as measured by the central laboratory (a
normal C1q level in HAE was an eligibility criterion), the central laboratory
was changed 3 times during the pivotal study.
Also, the method used for measurement of serum C4 was changed during the
study.
h.
Part B
(prophylaxis) enrolled subjects who had completed Part A, and who had
demonstrated a high frequency of HAE attacks.
Subjects were randomized to 12 wks prophylaxis with either C1INH or
placebo (infused at study site), followed by a cross-over to 3 months
prophylaxis with the other study agent.
HAE attacks of any severity were recorded.
i.
Presence of abnormally high levels of antibody against C1INH
was an exclusion criterion.
Due to aberrations of laboratory determinations
of complement and
antibody against C1INH, patients were
enrolled and then adjudicated for
diagnosis (if C4 levels did not decline
during acute attack) and granted a
waiver (if baseline antibody levels were high
but restested negative). This
involved 10/22 patients in Part B.
2.22. Safety Monitoring
In Part A (treatment of HAE attacks), subjects were monitored at the clinical site for 12 hours after treatment. If HAE attack symptoms persisted, subjects could be hospitalized until complete resolution of symptoms, if necessary. Subjects were contacted by telephone 72 hours after treatment to obtain follow up information on HAE attack parameters (e.g. time to complete resolution) and for adverse events.
In
Part B (prophylaxis of HAE attacks), subjects received prophylaxis treatments 2
or 3 times a week at the clinical site.
Adverse event information was collected at each visit. In addition, subjects were given diary cards
to record information on HAE attacks and adverse events. Subjects were contacted at least once a week
by telephone and were questioned about HAE attacks and adverse events. All subjects had a follow up visit 3 months
after the final prophylaxis treatment to provide a blood sample for evaluation
of viral safety.
2.23.
Pharmacokinetic Study: 2006-5
Pharmacokinetics (PK) were performed as a randomized, parallel group, open label
study in 27 subjects (1 to 46 years of age) with hereditary angioedema (HAE).
The subjects received either 1 dose (1000 units Cinryze IV; n = 13) or 2 doses (1000 units dose followed by a second 1000 units dose one hour later; n = 14). Blood samples were taken before dosing and at regular intervals for 168 hours (5 minutes, 1, 3, 6, 24, 48, 96, and 168 hours). Plasma concentrations of antigenic C1 inhibitor, functional C1 inhibitor, and C4 antigen were measured for PK evaluation.
The following table summarizes the PK parameters of Cinryze (functional C1 inhibitor):
Table 1: Pharmacokinetic
parameters of Cinryze (functional C1INH), mean ± SD
|
Parameters |
Single Dose (n = 13) |
Double Dose (n = 14) |
|
Cbaseline (U/mL) |
0.31 ± 0.20 |
0.33 ± 0.20 |
|
Baseline corrected Cmax (U/mL) |
0.37 ± 0.15 |
0.51 ± 0.19 |
|
Baseline corrected AUC(0-∞) (U*hr/mL) |
24.5 ± 19.1 |
39.1 ± 19.9 |
|
CL (mL/min) |
0.85 ± 1.07 |
1.17 ± 0.78 |
|
Half-life (hours) |
56 ± 36 |
62 ± 38 |
|
Mean residence time (MRT) hrs |
84 ± 50 |
91 ± 52 |
Plot of Cinryze plasma concentrations vs.
time (functional C1INH activity)

FDA Conclusions:
The PK of Cinryze in subjects with HAE indicates that the drug has a long half-life and slow clearance. Administration of the second dose of Cinryze 60 minutes after the first dose did not follow linear kinetics (Cmax and AUC were not dose proportional). The long half life indicates that a dose schedule of 2 administrations per week is reasonable and would likely result in C1INH levels > 40% of normal which are considered sufficient to prevent attacks.
3.0 CLINICAL
OVERVIEW OF PART B, PROPHYLAXIS
Study Objectives and Endpoints
The objective of
this Part B study was to investigate efficacy and safety of Cinryze™ as a
prophylactic treatment to prevent HAE attacks (Part B).
The primary
endpoint for Part B was the number of attacks of HAE during each treatment
phase (normalized for the number of days the subject participated in this
phase), using each subject as his/her own control. The normalized number of
attacks was calculated by dividing the total number of attacks in each period
by the number of days the patient was in that period.
The secondary
efficacy endpoints for Part B were the number of subjects dropping out at
each treatment period, average severity of attacks, average duration of
attacks, number of open-label C1INH-nf infusions, and change from baseline in
C1INH antigenic and functional levels.
The following tables present
information on the clinical studies that have been conducted with CinryzeTM.
Only the efficacy results of study
2005-1 Part B (prophylaxis of HAE attacks) will be presented at the May 2,
2008, Blood Products Advisory Committee meeting.
It should be noted that there were
no adequate and well-controlled studies of Cinryze™ or the European product
version, CETOR, prior to study 2005-1.
The European product version of Cinryze™ was licensed based on data from
a pharmacokinetics study. --------------------------- --------------------------------------------------------------------------------------------------------------------------------------------------------
Table 2: Completed
Safety and Efficacy Studies with Cinryze (C1INH) Conducted by Lev
Pharmaceuticals, Inc. (Part A)
|
Study Number Drug Indication |
Study Design |
Dose |
Placebo |
Cinryze |
Open Label Cinryze Onlya |
Safety |
Efficacy |
|
LEVP 2005-1 PART/A Cinryze HAE |
Phase III, multi-center, randomized,
placebo- controlled, double- blind study to evaluate the efficacy and safety of Cinryze (C1INH-nf) as a therapeutic
agent for acute attacks
of HAE |
Cinryze: 1000
U or 2000
U |
Randomized: 35
subjects As
Treated b 34
subjects M:6 F: 28 Age: 9-64 years Safety: 35 M:7 F:28 Age9-64 Years |
Randomized: 36
subjects As
Treatedb: 37
subjects M:10 F:
27 Age:
6 -75 Years Safety: 36 M:9 F:27 Age:6-75 Years |
12
subjects M:
6 F:
6 Age:
9 -73 Years Safety: 12 M:9 F:27 Age:6-75 Years |
AEs clinical laboratory, vital
signs local tolerance |