FDA Briefing Document

 

Blood Products Advisory Committee Meeting

 

May 1-2, 2008

 

 

 

 

 

 

 

 

 

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 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 U.S. studies conducted under IND ------:

 

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 before 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.

 

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.  Postmarketing studies will be needed to resolve this issue.

 

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). 

 

Conclusion

 

CinryzeTM at a potency of 1000 units 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)

 

Fig 4. Upper figure: diagrammatic representation of plasma kinin-forming cascade indicating steps inhibitable by C1 INH. 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 C1 INH.

 


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% 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 U.S. licensed C1 Esterase Inhibitor products at the present time.

 

The following summarizes the regulatory chronology of this BLA:

 

13-May-2004  Pre-IND meeting on manufacturing and clinical trial design

27-Jul-2004     Pre-IND meeting on manufacturing and clinical trial design

28-Jul-2004     IND ------ submitted

16-Jan-2004    Orphan designation was granted for "treatment of angioedema."

07-Jan-2005    Telecon on conformance lots, request for permission to do PK in phase 4, and viral safety testing

01-Feb-2005    Telecon on viral safety testing

30-Oct-2005    Fast Track designation granted

21-Jun-2007    Pre-BLA telecon on assay problems

31-Jul-2007     STN125267 submitted

14-Aug-2007   Review Committee: Felice D’Agnillo – Chair, Charles Maplethorpe – Clinical, Paul Buehler – Nonclinical, Boris Zaslavsky – Statistician, Robert Wesley – BIMO, Dave Doleski - CMC, Facility, Mahmood Farshid – Product (Virus Removal), Jean Makie – APLB, Elena Karnaukhova – CMC, Product, Omer Butt – CMC, Product, and Joseph Quander - Lot Release

15-Aug-2007   Priority Review granted

25-Sep-2007    FDA information request faxed to sponsor (data vetting, observation times, response modeling request, CMC, clinical pharmacology, labeling)

29-Sep-2007    Filing Date

17-Oct-2007    Sponsor’s response to 25-Sep-2007 FDA fax [see Appendix 2]

29-Oct-2007    Sponsor submits results of Part B (prophylaxis)

27-Nov-2007   Sponsor’s response to 07-Nov-2007 FDA fax

30-Jan-2008    First Action Due Date

 

2.2              BASIS FOR LICENSURE

 

The applicant conducted a phase 3 study 2005-1 having 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 it is discussed below.

 

2.21     Brief Synopsis of Study Procedures for Part A

and for Part B

 

Enrolled subjects who had completed Part A (treatment of acute attacks), and who had demonstrated a high frequency of HAE attacks (2 or more per month).  Subjects were randomized to 90 d prophylaxis with either C1INH or placebo (infused at study site), followed by a cross-over to 90 d prophylaxis with the other study agent.  HAE attacks of any severity were recorded. Subjects in either arm received open label C1INH, 1000 U, during acute attacks while on the prophylaxis part of the study. Since enrollment in the prophylaxis study (Part B) depended on their 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 they 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 90 d 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: Mean pharmacokinetic parameters of Cinryze (functional C1INH)

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 avoid 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.

 

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

antigenicity

viral serology

Primary:

Time to the

beginning of

unequivocal relief

 

Secondary:

Percentage of

subjects who had

unequivocal

beginning of relief within 4 hours following

treatment; time to complete resolution

of the attack;

effects of treatment

on CIINH and C4 levels.

a Subjects treated for non-randomizable attacks only. Randomized subjects could also receive Cinryze for non-randomizable attacks prior to or after the attack evaluated in the double-blind part of the study

bSubject 22-001 randomized to the placebo treatment group received ClInh-nf in error at 60 minutes. Therefore, he was included in the Cinryze treatment group in the “As Treated” population.

 

This study was submitted to the FDA as Part A and is currently under review.
Table 3:

 

Study Number

Drug

Indication

Study Design

Dose

Study Population

Open Label

Cinryze

Only

Safety

Efficacy

-

LEVP 2005-1 PART/B

Cinryze

HAE

Phase 3, multicenter, randomized, placebo-controlled, double-blind cross-0ver study to evaluate the efficacy and safety of Cinryze (C1INH-nf) for prevention of acute attacks of HAE

Cinryze: 1000 U or Placebo (2 infusions per week) in 2 12-week periods

Randomized and Treated: 24

 

Placebo/Cinryze: 12

 

Cinryze/Placebo: 12

2 subjects

 M: 0

F: 2

Age: 4l- 53

 

AEs, clinical laboratory, vital signs, antigenicity, viral serology

Primary:

-Number of attack of angioedema

 

Secondary:

-Number of withdrawals

-Total number of days of swelling

-Average severity of attacks,

-Average duration of attacks,

-Number of open label Cinryze infusions,

-Average number of days of swelling, Effect of treatment on C1INH levels

Efficacy Dataset

22 Subjects

M:2

F:20

 

Age:9-73

Years

Safety Dataset

(randomized):24

M:3

F:21

 

Age:9-73

Years

Safety: 2 subjects

 

This is the prophylaxis study submitted to the FDA as Part B, and is the subject of this BPAC presentation.
Table 4:  Completed Clinical Pharmacology Studies with Cinryze (C1INH) Conducted by Lev Pharmaceuticals, Inc.

 

Study Number

Drug

Indication

Study Design

Dose

Treated

Demographics

Safety Data

Other

Outcomes

LEVP 2006-5 PART/B

Cinryze

HAE

Phase 1, randomized, parallel-group, open-label study to compare the PK of a single dose of Cinryze (C1INH-nf) to that of 2 doses

Cinryze

1 or 2 doses at

1000 U

27 subjects

1 dose

(13 subjects)

2 doses

(14 subjects)

M:10

F:17

Age:19-57

Years

AEs, clinical laboratory, vital signs, and virology

PK of antigenic and functional C1INH-nf:

PK of C4

 

This is the PK study described in the text (see above 2.23)

 

 

Table 6:  Ongoing Safety and Efficacy Studies with Cinryze (C1INH) Conducted by Lev Pharmaceuticals, Inc.

 

Study Number

Drug

Indication

Study Design

Dose

Duration

Enrolled

Treated

Demographics

Safety Data

Data Available

as of

25 Sep 2007

    Efficacy

LEVP 2006-1

HAE

Phase 3, multi-center, open-label

study of CinryzeTM (C1INH-nf)

for the treatment of HAE attacks

Cinryze:

1 or 2 infusions

1000 U /infusion

67 subjects

67 subjects

M:18

F:49

Age: 7-81

Years

SAE s

Number of subjects with

unequivocal beginning

of relief within 4 hours.

Time to the unequivocal

beginning of relief,

change in time to the

unequivocal beginning

of relief

C1INH and C4 levels.

LEVP 2006-4

HAE

Phase 3, multi-center, open-label

study that will evaluate the

efficacy and safety of Cinryze

(CIINH-nf) as prophylaxis to

prevent HAE attacks.

Cinryze :

1000 U every 3

to 7 days

46 subjects

46 subjects

M:5

F:41

Age:5-75

Years

SAE s

Number of attacks

PK/PD analyzed under

separate protocol

 

 

These studies are under IND and facilitate access to the product in the USA.
3.1       EFFICACY – PIVOTAL STUDY Part B – Prophylaxis of HAE Attacks

 

Study 2005-1 Part B was a pivotal study of the use of  CinryzeTM for prophylaxis of HAE attacks.  Subjects for Part B were selected from among subjects who had completed study 2005-1 Part A, treatment of HAE attacks.   Subjects who demonstrated a high frequency of HAE attacks (2-3 per week) during the monitoring period for Part A were enrolled into Part B.

 

Subjects in Part B were randomized to receive intravenous treatments 2 to 3 times per week for 90 days with 1000 U CinryzeTM or a matched dose of placebo, administered at a clinical site under a blinded clinical trial design.  At the end of the 90 day prophylaxis period, subjects were crossed over, without a washout period, to the other prophylaxis arm (CinryzeTM or placebo) for an additional 90 day period.   Subjects in either arm received open label C1INH during acute attacks, 1,000 U, while on the prophylaxis part of the study. Subjects recorded the incidence and severity of all HAE attacks experienced during each prophylaxis period in a diary or reported at a scheduled visit.

 

The actual length of the period of prophylaxis varied among subjects and treatment periods, but was approximately 90 days.

 


Sponsor’s Efficacy Analyses: Part B

 

Primary

 

The primary efficacy endpoint for Part B was the number of attacks of angioedema during each treatment period, normalized for the number of days the subject participated in that period. This was done by dividing the total number of attacks in each period by the number of days the patient was in that period. An attack is defined as the subject-reported indication of a new swelling at any body location following a report of no swelling at that body location on the previous day.

 

Secondary

 

The secondary efficacy endpoints for Part B were:

 

           number of subjects dropping out at each treatment period.

           average severity of attacks. (The severity of an attack was the highest value assigned by the subject to any location at any day during the attack.)

           average duration of attacks. (The duration of an attack was measured from the first report of swelling at any location until a subsequent report of no swelling at the same location.)

           number of open-label C1INH-nf infusions.

           change from baseline in C1INH antigenic and functional levels

 

Other Evaluations

 

The total number of days of swelling in each study period was compared between C1INH-nf and placebo.

 


 

 

 

Table 7: Part B – results of prophylaxis of HAE attacks (n = 22):

 

Subject

Attacks

on

C1INH

C1INH
Period

Length

(Days)

C1INH

Attack

Frequency
(Attacks/Day

Attacks

on

Placebo

Placebo
Period

Length

(Days)

Placebo

Attack

Frequency
(Attacks/Day

Percent
Reduction in

Number of

Attacks

 

Percent
Reduction in
Attack
Frequency

06-001

0

81

0

6

85

0.07059

100%

100.0%

12-005

0

34

0

7

96

0.07292

100%

100.0%

24-001

0

81

0

14

82

0.17073

100%

100.0%

59-001

0

83

0

14

80

0.175

100%

100.0%

16-004

2

84

0.02381

22

96

0.22917

91%

89.6%

12-012

1

82

0.0122

9

86

0.10465

89%

88.3%

07-001

2

81

0.02469

13

83

0.15663

85%

84.2%

16-003

2

81

0.02469

12

85

0.14118

83%

82.5%

53-002

2

81

0.02469

9

81

0.11111

78%

77.8%

06-018

2

85

0.02353

8

82

0.09756

75%

75.9%

51-001

8

81

0.09877

20

82

0.2439

60%

59.5%

13-002

10

85

0.11765

19

86

0.22093

47%

46.7%

53-003

7

82

0.08537

14

93

0.15054

50%

43.3%

18-004

7

82

0.08537

10

67

0.14925

30%

42.8%

53-001

11

81

0.1358

17

85

0.2

35%

32.1%

16-006

13

81

0.16049

19

82

0.23171

32%

30.7%

56-001

6

80

0.075

8

80

0.1

25%

25.0%

52-001

12

82

0.14634

15

81

0.18519

20%

21.0%

07-012

12

82

0.14634

14

86

0.16279

14%

10.1%

54-001

6

85

0.07059

6

84

0.07143

0%

1.2%

16-005

17

81

0.20988

16

82

0.19512

-6%

-7.6%

17-002

15

86

0.17442

8

85

0.09412

-88%

-85.3%

 

The sponsor has presented these outcomes (Table 8a) by pooling data within a prophylaxis period and reporting mean values for attack frequency comparing CinryzeTM to placebo (6.1 vs. 12.7)  suggesting a 50% reduction in HAE attack frequency while on CinryzeTM prophylaxis.

 


Table 8a: Results of Part B – Prophylaxis
(Sponsor’s Analysis)

 

Statistic

Cinryze

(N=22)

Placebo

(N=22)

Number of attacks (90d)

Mean

6.1

12.7

 

SD

5.43

4.80

 

Median

6.0

13.5

 

Min

0

6

 

Max

17

22

 

Table 8b: Results of Part B – Prophylaxis
(Sponsor’s Analysis)

 

Generalized Estimating Equation (GEE) Analysis Results

Treatment Effect p-value

<.0001

Sequence Effect p-value

0.3347

Period Effect p-value

0.3494

 

Table 8b is the pre-specified ANOVA using each individual as his/her control in the crossover study.  FDA has verified these calculations showing a highly significant treatment effect.  Even if 10/22 patients, showing aberrant C4 and/or antibody levels are excluded from the efficacy analysis, the treatment effect was statistically significant (p =0.0004).

 

As can be seen from Table 7, and the histogram below, treatment with CinryzeTM  resulted in varying reductions in HAE attack frequency: 45 % (10/22) of individuals had a reduced attack frequency of  >75%; 32% (7/22) had intermediate reductions (25-75); and 18% (4/22) had modest reductions (1-25%) in attack frequency.  Two individuals (9%) had more attacks with CinryzeTM than with placebo.

 

 

 

 

One explanation for the diversity in responsiveness could be that the dose used was not optimal.  At a pre-IND meeting in 2004 FDA recommended phase 2 studies that may have facilitated more optimal dosing for the phase 3 trial.  The sponsor declined, citing the rarity of the disease and the difficulty in conducting such phase 2 studies.

 

Efficacy: Secondary Endpoints

 

Among the secondary endpoints analyzed by the sponsor were number of drop-outs, average attack severity, average duration of attacks, number of open-label C1INH-nf infusions, change from baseline in C1INH antigenic and functional levels, total number of days of swelling in each study period.

 

Attack severity and attack duration are related to clinical benefit and appear to be relatively independent.  Other secondary endpoints – such as days of swelling and number of open label C1INH infusions -- appear not to be independent of the primary endpoint and the secondary endpoints relating to attack duration and severity.  In addition, the secondary endpoint of C1INH levels must be considered an unvalidated surrogate endpoint at this time.

 

For the secondary endpoints attack severity and attack duration the following tables give these results:

 

Attack Severity Scale

 

·         Mild – Events that were usually transient, required no special treatment, and did not interfere with the subject’s daily activities.

·         Moderate – Events that introduced some level of inconvenience or concern to the subject, and may have somewhat interfered with daily activities, but were usually ameliorated by simple therapeutic measures (may have included drug therapy).

·         Severe – Events that were unacceptable or intolerable, significantly interrupted the subject’s usual daily activity, and required systemic drug therapy or other treatment.


Table 9:
Average Severity of HAE Attacks

During Prophylaxis Period

Subject

C1INH-nf

Placebo

06-001

0.0

1.7

06-018

1.0

2.0

07-001

1.0

1.6

07-012

2.6

2.5

12-005

0.0

1.9

12-012

1.0

1.7

13-002

1.5

2.1

16-003

1.0

1.6

16-004

2.0

2.3

16-005

1.7

1.9

16-006

1.2

1.9

17-002

2.6

2.0

18-004

1.9

2.2

24-001

0.0

2.5

51-001

1.5

1.7

52-001

1.4

1.7

53-001

1.3

1.6

53-002

3.0

1.3

53-003

1.0

1.8

54-001

2.0

2.7

56-001

1.5

1.5

59-001

0.0

1.9

 

 

 

Average

1.3

1.9

p = 0.006

 

Table 10: Average Duration (Days) of HAE Attacks

During Prophylaxis Period

Subject

C1INH-nf

Placebo

06-001

0.0

3.7

06-018

2.0

8.3

07-001

3.0

3.8

07-012

3.7

3.5

12-005

0.0

2.1

12-012

3.0

2.2

13-002

2.7

3.4

16-003

3.5

2.8

16-004

2.5

3.0

16-005

2.5

3.3

16-006

2.5

3.6

17-002

3.5

4.6

18-004

2.0

3.2

24-001

0.0

2.8

51-001

2.5

3.1

52-001

2.2

2.1

53-001

2.5

3.0

53-002

2.5

2.4

53-003

2.3

5.8

54-001

2.0

2.5

56-001

2.3

2.8

59-001

0.0

2.2

 

 

 

Average

2.1

3.4

p = 0.0005

 

FDA Comment

 

FDA analyzed these data (see below under 3.4 FDA Statistical Review) and

found that for the secondary endpoints, treatment with CinryzeTM compared to

placebo reduced the severity and duration of attacks, and that these effects

were statistically significant.

 

A gender imbalance was noted over the course of the study. In Part A the C1INH arm had 36 subjects (26 female, 9 male, 1 gender unknown), the placebo arm had 35 subjects (27 female, 7 male, 1 gender unknown).  In Part B there were 2 males and 20 females.

  

The genetic defect is autosomal dominant, which predicts an even distribution between males and females.  One possible explanation for the imbalance of subjects enrolled in Part A is that females disfavor the current standard preventive therapy with attenuated androgens and might therefore be more likely to seek entry into clinical trials of new treatment and prophylactic therapies for HAE.  Additionally, estrogens predispose females to a higher frequency of attacks.  At screening for Part A the average time between attacks for enrolled subjects was reported as every 36 days for 69 males, and every 26 days for 168 females.  Selection in Part B was determined by an increased frequency of attacks in Part A. Thus the further selection of females in Part B could be explained on the basis that they experienced more frequent attacks. 

 

Given the clinical observations that females have more frequent and more severe HAE attacks than males, the demonstration of successful HAE prophylaxis in this study cohort of mainly female subjects  is statistically significant (p < 0.0001). There is no reason to suspect that Cinryze would not be at least as effective in males, who typically have milder disease manifestations.

 

Efficacy Conclusion.

Overall, FDA concludes that CinryzeTM has been demonstrated to be effective for reduction of the frequency of HAE attacks when used for prophylaxis in persons with hereditary angioedema.

 

IMMUNOGENICITY

 

Immunogenicity was evaluated in Part A (treatment of HAE attacks) and in Part B (prophylaxis of HAE attacks). 

 

In Part A 93/329 subjects (28%) were antibody positive at screening or pre-infusion at the first laboratory used by the sponsor.  At 3 months, 6 of 236 (2.5%) subjects that were previously antibody negative, tested positive.  A subset of samples from these subjects were retested at a second laboratory and 2/119 (0.8%) were positive, whereas 58/119 (49%) tested positive at the first laboratory.  A smaller number of samples, n = 11, were sent to a third laboratory and all tested negative, although 5 of 11 were positive in the first laboratory.

 

All 24 subjects in Part B were first enrolled in Part A. Of the 22 subjects who completed Part B, 8 exhibited a positive result for C1INH antibodies at the end of Part B and/or at the 3 month follow-up. Of these 8 subjects, 3 reported a positive result (bound and/or free Ab) at screening or at pre-infusion of C1INH.

 

Of the remaining 5 subjects, 3 had modest elevations in antibody levels (less than 60% of the positive control).  However, 2 subjects (Patients 59-001 and 16-005) appeared to have a notable antibody response (95% and 125% of the positive control). Since these are binding assays, not functional assays, it is not known whether these antibodies have neutralizing activity. The effect of this antibody response on treatment efficacy is difficult to assess. Patient 59-001 still showed a 100% reduction in attack frequency on CinryzeTM, while Patient 16-005 showed an increase in attack frequency.

 

There was no evidence that the antibody levels correlated with adverse events or treatment effects of CinryzeTM (Table 11, Appendices 2, 3).  However, it will be necessary to resolve this issue with post-marketing studies.

 

Table 11: Lack of Relationship between

Positive anti-C1INH antibody

Results and Percent Reduction
in HAE attack frequency

 

Subject

Any

Positive

anti-C1INH

Antibody

Percent

Reduction

in HAE Attack

Frequency

24-001

Y

100%

59-001

Y

100%

16-004

Y

90%

07-001

Y

84%

16-003

Y

83%

53-002

Y

78%

06-018

Y

76%

53-003

Y

43%

16-006

Y

31%

56-001

Y

25%

52-001

Y

21%

07-012

Y

10%

16-005

Y

-8%

06-001

N

100%

12-005

N

100%

12-012

N

88%

51-001

N

60%

13-002

N

47%

18-004

N

43%

53-001

N

32%

54-001

N

1%

17-002

N

-85%

 

 

3.3 SAFETY

 

Safety analyses were assessed using the following measures: extent of exposure, AEs, vital signs, physical examinations, and laboratory tests. All summary safety analyses were carried out using subjects included in the safety dataset.

 

After review of the submitted safety databases, we conclude there are no safety concerns for use of Cinryze for prophylaxis to prevent HAE attacks at the doses studied.

 

The safety data for study 2005-1 Parts A (treatment of HAE attacks) & Part B (prophylaxis of HAE attacks), and for other studies conducted with Cinryze or its earlier product versions, are attached in appendices 2, 3, and 4.

 

Study 2005-1 Part A observed 32 adverse events that occurred in 18 subjects of 71 subjects treated for an HAE attack (7 C1INH, 11 placebo), as shown appendix 3.  There were no deaths and no serious adverse events.

 

Study 2005-1 Part B observed 117 adverse events in 21 subjects of 22 subjects who completed both periods of the prophylaxis study. 

 

The higher rate of reported adverse events and the higher proportion of subjects who experienced an adverse event in Part B compared to Part A can be attributed to

1)      the much longer observation period for Part B (90 days) compared to Part A (12 h, or in hospital, and at 3 months follow up), and

2)      less intense monitoring for adverse events in Part A than in Part B (in which subjects returned to the clinic every 2 or 3 days for an infusion).

 

In study 2005-1 Part B (prophylaxis of HAE attacks), the attribution of adverse events to the treatment administered is complicated by the protocol provision for open-label treatment with C1INH once an HAE attack had occurred.  It is not unexpected that more adverse events were reported following administration of Cinryze since (i) Cinryze was administered open label at the time of an attack and at a time when adverse events related to the attack would be expected to occur and be reported; and (ii) because of open label use Cinryze was given more frequently than placebo (see Table 13 below).   

 

In study Part B, the sponsor appropriately attributes all adverse events to the study agent C1INH. An alternative approach is to attribute the adverse event to the agent that was administered immediately prior to the onset of the adverse event (i.e. treatment emergent adverse events).  Using this latter approach, the following table of adverse events can be derived:

 

Table 12:  Adverse Events by Organ System and by Previously Infused Study Agent

 (Number of Adverse Events, Number of Subjects experiencing the Adverse Event)

 

Organ System

C1INH-nf

AE

C1INH-nf

Subjects

Placebo

AE

Placebo

Subjects

Blood and lymphatic system disorders

2

2

 

 

Congenital, familial and genetic disorders

2

2

 

 

Eye disorders

1

1

1

1

Gastrointestinal disorders

7

6

4

3

General disorders and administration site conditions

3

3

1

1

Infections and infestations

29

12

17

10

Injury, poisoning and procedural complications

7

3

4

1

Investigations

2

1

 

 

Metabolism and nutrition disorders

 

 

1

1

Musculoskeletal and connective tissue disorders

6

5

1

1

Nervous system disorders

6

5

 

 

Psychiatric disorders

 

 

1

1

Reproductive system and breast disorders

1

1

 

 

Respiratory, thoracic and ediastinal disorders

4

4

4

3

Skin and subcutaneous tissue disorders

10

6

2

2

Vascular disorders

1

1

 

 

Grand Total

81

20

36

13

(see Appendix 4 for a list of the adverse events)

 

Although it would appear that there is an increased frequency of adverse events after CinryzeTM administration, it must be re-emphasized that the study design and the provision for open label administration of CinryzeTM  after an HAE attack resulted in patients being exposed to CinryzeTM more frequently than placebo (1190 Cinryze infusions vs. 526 placebo infusions).  

 

 

Serious Adverse Events

 

There were no deaths during study 2005-1 Part B.  There were 4 serious adverse events (SAEs) in study 2005-1 Part B (see Appendix 4 for details). The SAEs are summarized as follows:

Subject 51-001 SAE: HAE attack

SAE: Surgery for peri-auricular cyst and insertion of permanent subcutaneous port

The Investigator categorized these events as moderate in intensity and not related to study medication

 

Subject 53-003 SAE: HAE attack

The Investigator categorized this event as severe and not related to the study medication.

 

Subject 55-001 SAE: HAE attack

The Investigator categorized this event as moderate and not related to the study medication.

 

Subject 13-002 SAE: Laryngeal edema

The Investigator categorized this event as severe and not related to the study medication and related to HAE.

 

Safety Conclusion.

 

The adverse events appear to be related to intercurrent illnesses and the underlying disease rather than being due to treatment with CinryzeTM.  The small number of skin, hypotensive and pulmonary events, suggest that immune responses to the product, if they occurred, were not associated with typical hypersensitivity reactions. Therefore, CinryzeTM appears to have an acceptable safety profile for prophylaxis of HAE attacks when administered according to the labeled dose schedule.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

3.4 FDA STATISTICAL REVIEW

 

The Biologics Licensing Application (BLA) contains a well-controlled phase 3 study LEVP 2005-1 conducted under IND ------. The study consists of two parts to investigate the efficacy and safety of C1INH-nf for the treatment of Hereditary Angioedema (HAE) in acute attacks (Part A) and a prophylactic treatment to prevent HAE attacks (Part B). This statistical briefing document discusses only the results from LEVP 2005-1 Part B (prophylaxis of HAE attacks) study. 

 

Study Design

 

It is a Phase 3 multi-center, randomized, placebo-control, double-blind trial to confirm the efficacy of prophylactic C1INH-nf in the prevention of acute attacks of HAE in patients. Subjects were not to enter Part B until either they had completed their randomized treatment in Part A or Part A had ended. Each subject was randomized to receive either 90 days of C1INH-nf followed by 90 days of placebo, or 90 days of placebo followed by 90 days of C1INH-nf, administered at a clinical site under a blind.  At the end of the 90 day prophylaxis period, subjects were crossed over, without a washout period, to the other prophylaxis arm (Cinryze or placebo) for an additional 90 day period.   Subjects recorded the incidence and severity of all HAE attacks experienced during each prophylaxis period. The study enrolled 24 subjects. Two subjects did not go to the second period. The sponsor’s analysis was based on 22 subjects.

 

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.

 

Results from Applicant

Summary statistics consist of frequencies and percentages of responses in each category for discrete measures and of means, medians, standard deviations, minimum and maximum values for continuous measures. All significance tests were two-sided with statistical significance at the 5% level.

 

 


Primary Endpoint: Number of HAE Attacks

 

Table 13: Summary statistics of Part B – Prophylaxis

Statistic

Cinryze

(N=22)

Placebo

(N=22)

Mean

6.1

12.7

SD

5.43

4.80

Median

6.0

13.5

Min

0

6

Max

17

22

 

 

For crossover analyses, a standard analysis of variance was performed with effects for treatment, period, and subject within treatment. The crossover analysis evaluating the number of attacks was based on Poisson assumption and used the SAS PROC GENMOD. All significance tests were two-sided with statistical significance at the 5% level. The difference in the number of attacks during treatment with Cinryze and treatment with Placebo was statistically significant.

 

Table 14: The crossover analysis evaluating the number of attacks

 

Treatment Effect p-value

<.0001

Sequence Effect p-value

0.3347

Period Effect p-value

0.3494

 

 

Efficacy Secondary Endpoints:

 

For the secondary endpoints attack severity and attack duration the following tables give these results:

 

 

Table 15: Average Severity of HAE Attacks. Attack Severity Scale:

1 = mild, 2 = moderate, 3 = severe

 

 

C1INH-nf

Placebo

Difference

Mean

1.33

1.89

-0.56

SD

0.85

0.36

0.69

Median

1.35

1.9

-0.6

 

The p-value reported by the sponsor was p=0.006. Using the paired t-test, we found that the difference was statistically significant (p=0.0056)

 

Table 16: Average Duration of HAE Attacks (Days):

 

 

C1INH-nf

Placebo

Difference

Mean

2.14

3.37

1.23

SD

1.13

1.4

1.28

Median

2.5

3.05

-0.75

 

The p-value reported by the sponsor was p =0.0005. Using the paired t-test, we found that the difference was statistically significant (p=0.0023).

 

The applicant concluded that since the difference in the number of attacks during treatment with Cinryze and treatment with placebo was statistically significant, that efficacy had been demonstrated.

 

 

Reviewer’s comments and analysis

 

The applicant provided the reviewer with the datasets and SAS programs used in their statistical analysis. The SAS programs have been found correct. From the results obtained the by the reviewer, the difference in the number of attacks during treatment with Cinryze and treatment with Placebo was statistically significant.  Hence, the primary objective of the study has been achieved. The difference in secondary endpoints was also confirmed to be statistically significant.

 

Reviewer Overall conclusion

 

The efficacy results based on the Generalized Estimating Equations (SAS PROC GENMOD with Poisson distribution and log link function) were confirmed by the reviewer, who considered them to be appropriate for the analysis of the number of attacks. The reviewer concluded that the applicant demonstrated effectiveness of CinryzeTM for reduction of the frequency of HAE attacks when used for prophylaxis in persons with hereditary angioedema.

 

 

 

 

 

 

 

 


3.4  QUESTIONS TO THE COMMITTEE

 

Question #1

 

Is the evidence on safety and efficacy 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 resolve the following:

 

a)      the optimal dose for prophylaxis in males and females

b)     immunogenicity

 

 

 

 


 

 

 

Appendix 1.         Adverse Events in Studies conducted by Sanquin BSF using an earlier version of the product (CETOR) that is currently licensed in Europe

 

There were no deaths in studies conducted by Sanquin BSF using CETOR.

 

Adverse Events in Studies Conducted by Sanquin BSF

 

Subject

ID

Treatment

AE

Preferred Term or Verbatim

Severity

Relationship

036-005/Part A

N = 9

AEs=1

RGG2

Cetor

Fatigue

unknown

unknown

KB97002-C1-INH

N=22

AEs=17

101

Cetor

Mitral insuff Grade II III

mild

Not related

102

Cetor

Bleeding from wound of teeth extraction

under anticoagulation

mild

Not related

Headache

moderate

Not related

103

Cetor

Edema because of subcutaneous infusion

of C1-INH

moderate

Not related

104

Cetor

Exanthema arms & thorax mild edema

fingers, allerg.  react.  to streptokinase

moderate

Not related

 

 

Slightly elevated levels of CL, G-GT,

ALAT&CRP No clinical relevance.

mild

Not related

105

Cetor

Serious complaints during infusion due to

Phlebitis

severe

Not related

107

Cetor

PTCA because of pending MI

severe

Not related

Headache

mild

Not related

108

Cetor

At discharge ALAT outside normal range

without clinical. relevance

mild

Not related

109

Cetor

Mitral insufficiency grade 2-3, diagnosed

Through echo

moderate

Not related

110

Cetor

LD, G-GT and ALAT outside normal

range, no clin. relevance

mild

Not related

Mitral valve insufficiency grade 1

diagnosed through echo

mild

Not related

Suspicion of hypercholesterolaemia

mild

Not related

111

Cetor

Mild allergic reaction to strepto

exanthema, itching, edmea

severe

Not related

ASAT&ALAT slightly outside normal

range, no clinical. relevance

mild

Not related

112

Cetor

Phlebitis on site of infusion

mild

Not related

113

Cetor

Gastric complaints, subject has a history

of gastic ulcers;

mild

Not related

Reinfarction

severe

Not related

114

Cetor

Mitral valve insufficiency Grade 1-2

mild

Not related

115

Cetor

Mitralis insufficiency II-III, diagnosis

through echocardiograrn

moderate

Not related

116

Cetor

300-400 mL blood loss due to reopening

of puncture hole

severe

Not related

127

Cetor

Compartmental syndrome in upper leg a

week before the infarction

moderate

Not related

128

Cetor

Phlebitis

mild

Not related

KB2003.01/Part A

N=14

AEs=5

 

103

 

Injection Site Thrombosis

mild

unlikely

 

Influenza

moderate

Not related­

 

Hereditary Angioedema

severe

Not related

 

104

 

Influenza

moderate

Not related

 

Hereditary Angioedema

moderate

Not related

 

106

 

Hereditary Angioedema

mild

Not related

 

319

 

Angioneurotic edema

mild

Not related

 

320

 

Angioneurotic edema

mild

Not related

 

 


Appendix 2.         Adverse Events reported for study 2005-1 Part A – Treatment of HAE Attacks

 

There were 32 adverse events in database “AE” that occurred in 18 subjects (7 C1INH, 11 placebo), as shown in the following table:

`                                                                   No, of AEs(No. of Subjects)

Adverse Event

C1INH

placebo

Anaemia

 

1(1)

Anorexia

 

1(1)

Arthropod bite

 

1(1)

Blood pressure decreased

1(1)

1(1)

Bronchitis

1(1)

 

Chest pain

 

1(1)

Dermatitis contact

 

1(1)

Diarrhoea

1(1)

 

Fatigue

 

1(1)

Gastritis viral

1(1)

 

Gastroenteritis viral

 

1(1)

Headache

1(1)

 

Intra-abdominal haemangioma

 

1(1)

Nausea

1(1)

1(1)

Nephrolithiasis

 

1(1)

Pneumonia

1(1)

 

Renal cyst

 

1(1)

Sinusitis

4(3)

 

Splenic lesion

 

1(1)

Tetany

 

1(1)

Upper respiratory tract infection

1(1)

1(1)

Urinary tract infection

 

1(1)

Vertigo

 

1(1)

Vitamin B12 deficiency

 

1(1)

Vomiting

1(1)

 

Vulvovaginal mycotic infection

1(1)

 

TOTAL

14(13)

18(18)

 


Appendix 3.    Adverse Events in study 2005-1 Part B – Prophylaxis of HAE Attacks

 

Adverse Events by Organ System and by Previously Infused Study Agent

(Number of Adverse Events, Number of Subjects experiencing the Adverse Event)

Organ System

Adverse Event

C1INH-nf

AE

C1INH-nf

Subjects

Placebo

AE

Placebo

Subjects

Blood and lymphatic system disorders

Anaemia

1

1

 

 

Lymphadenopathy

1

1

 

 

Blood and lymphatic system disorders Total

 

2

2

 

 

Congenital, familial and genetic disorders

Hereditary angioedema

2

2

 

 

Congenital, familial and genetic disorders Total

 

2

2

 

 

Eye disorders

Blepharospasm

 

 

1

1

Conjunctivitis

1

1

 

 

Eye disorders Total

 

1

1

1

1

Gastrointestinal disorders

Abdominal pain

1

1

 

 

Constipation

1

1

 

 

Diarrhoea

1

1

 

 

Gastrointestinal pain

 

 

1

1

Gastroesophageal reflux disease

1

1

2

1

Nausea

1

1

 

 

Tooth disorder

1

1

 

 

Vomiting

1

1

1

1

Gastrointestinal disorders Total

 

7

6

4

3

General disorders and administration site conditions

Atrophy

1

1

 

 

Chest discomfort

 

 

1

1

Pain

1

1

 

 

Pyrexia

1

1

 

 

General disorders and administration site conditions Total

 

3

3

1

1

Infections and infestations

Acute sinusitis

1

1

1

1

Bronchitis

2

2

1

1

Bronchitis acute

 

 

1

1

Ear infection

1

1

 

 

Fungal infection

1

1

 

 

Gastritis viral

1

1

1

1

Gastroenteritis viral

 

 

2

2

Herpes simplex

1

1

 

 

Influenza

 

 

1

1

Nasopharyngitis

1

1

2

2

Otitis media

2

1

 

 

Pneumonia

1

1

 

 

Sinusitis

8

5

4

3

Upper respiratory tract infection

3

3

1

1

Urinary tract infection

1

1

1

1

Vaginal candidiasis

1

1

 

 

Varicella

 

 

1

1

Viral upper respiratory tract infection

5

3

 

 

Vulvovaginal mycotic infection

 

 

1

1

Infections and infestations Total

 

29

12

17

10

Injury, poisoning and procedural complications

Contusion

 

 

1

1

Excoriation

1

1

 

 

Joint injury

1

1

 

 

Limb injury

2

2

 

 

Skin laceration

2

1

2

1

Thermal burn

 

 

1

1

Wound

1

1

 

 

Injury, poisoning and procedural complications Total

 

7

3

4

1

Investigations

Antibody test abnormal

2

1

 

 

Investigations Total

 

2

1

 

 

Metabolism and nutrition disorders

Vitamin B12 deficiency

 

 

1

1

Metabolism and nutrition disorders Total

 

 

 

1

1

Musculoskeletal and connective tissue disorders

Back pain

2

2

 

 

Musculoskeletal pain

1

1

 

 

Musculoskeletal stiffness

1

1

 

 

Pain in extremity

2

2

1

1

Musculoskeletal and connective tissue disorders Total

 

6

5

1

1

Nervous system disorders

Carpal tunnel syndrome

1

1

 

 

Dizziness

1

1

 

 

Headache

4

4

 

 

Nervous system disorders Total

 

6

5

 

 

Psychiatric disorders

Depression

 

 

1

1

Psychiatric disorders Total

 

 

 

1

1

Reproductive system and breast disorders

Vulvovaginal discomfort

1

1

 

 

Reproductive system and breast disorders Total

 

1

1

 

 

Respiratory, thoracic and mediastinal disorders

Cough

1

1

1

1

Laryngeal oedema

1

1

 

 

Nasal congestion

 

 

1

1

Pharyngolaryngeal pain

 

 

1

1

Postnasal drip

1

1

 

 

Rhinorrhoea

 

 

1

1

Sinus congestion

1

1

 

 

Respiratory, thoracic and mediastinal disorders Total

 

4

4

4

3

Skin and subcutaneous tissue disorders

Dermatitis contact

 

 

1

1

Erythema

1

1

 

 

Pruritus

2

2

 

 

Rash

7

5

1

1

Skin and subcutaneous tissue disorders Total

 

10

6

2

2

Vascular disorders

Poor venous access

1

1

 

 

Vascular disorders Total

 

1

1

 

 

Grand Total

 

81

20

36

13

 

The following is the sponsor’s narratives of the 4 serious adverse events that were observed during the Part B prophylaxis study:

 

Subject 51-001 SAE: HAE attack

 

SAE: Surgery for peri-auricular cyst and insertion of permanent subcutaneous port

 

Subject 51-001 was a 9-year-old White female subject. The subject had a history of frequent strep throat, a left per-auricular cyst, a rash and seasonal allergies. The subject participated in Part A of the study. The subject received her first dose of open-label study medication on 04 December 2005 and had multiple open-label infusions through 19 September 2006. She received her first dose of randomized study medication (Placebo) on 01 December 2005 and her first dose of double-blind Cinryze on 27 February 2006.

 

The subject had been having frequent abdominal HAE attacks, manifested by abdominal cramping and skin rash. On 17 February 2006, the subject complained of discomfort in her throat during gym class. She was taken to a local Emergency Department for treatment. A lateral neck radiography showed mild subglottic tracheal narrowing and edema. The angioedema attack was categorized as moderate in intensity. She was stabilized and was transferred to the ----------------------------------------------------------------------

 

The subject received 2 open-label doses of C1IHN infusion on 17 February 2006 for the treatment of this event. Her condition did not resolve immediately, and a decision was made to admit her to the hospital for additional treatment and observation. She received 2 more open-label doses of CIINH on 18 February 2006. Her condition improved after the second infusion on 18 February 2006. She was discharged to home the following day, fully recovered. No further laryngeal attacks have been reported.

 

The Investigator categorized the angioedema attack as moderate in intensity and not related to the study medication.

 

In March 2006, the subject had pre-auricular cyst of the left ear that became infected. She also had poor venous access. The cyst was treated for several weeks as an outpatient with oral antibiotic therapy. On 07 June 2006, she was hospitalized for surgical removal of the cyst and insertion of a permanent subcutaneous infusion port. The procedure was well tolerated and she was considered recovered upon discharge.

 

The Investigator categorized these events as moderate in intensity and not related to study medication.

 

The subject completed the study on 19 September 2006.

 

Subject 53-003 SAE: HAE attack

 

Subject 53-003 was a 64-year-old White female. The subject had a history of allergic rhinitis, hypertension, irritable bowel syndrome, sleep apnea, and osteoarthritis. The subject participated in Part A of the study.

 

In Part B, the subject had her first dose of randomized double-blind study medication (Cinryze) on 07 April 2006 and her last dose of randomized Cinryze on 27 June 2006. The subject had her first dose of open-label Cinryze on 03 July 2006. She had started the Placebo treatment phase on 11 July 2006.

 

The subject experienced an episode of severe angioedema while in the physician's office during an office visit on 17 July 2006. She stated that she had been in her usual state of health up until earlier in the day when she noted swelling on the left side of her face and neck, along with some difficulty in catching her breath. She received 2 doses of Cinryze and later reported that the difficulty in breathing lessened somewhat. Nevertheless, the facial and neck swelling continued. The subject became fearful, and requested admission to the hospital for observation.

The subject was observed overnight without any reported problems. The event was considered recovered upon discharge on 18 July 2006. The subject completed the study. The Investigator categorized this event as severe and not related to the study medication.

 

Subject 55-001 SAE: HAE attack

 

Subject 55-001 was a 41-year-old White female. She had participated in Part A of the study; in that part of the study she was identified as Subject 03-015. In Part A, she had her last treatment with Cinryze on 22 July 2006. This subject moved and was transferred to Site 55 with the intent to participate in Part B. However, prior to randomization at Site 55, this subject had an attack of HAE (described below). Thus, this event occurred after the completion of Part A and prior to randomization in Part B.

 

The medical history for this subject included diabetes mellitus and a tracheotomy.

 

The subject had several open-label infusions of Cinryze from 01 September 2006 to 28 September 2006. The subject did not receive any double-blind medication in Part B.

 

On 17 August 2006, the subject presented to the Emergency Department with an apparent acute exacerbation of hereditary angioedema, which was manifested by severe abdominal pain, nausea, and vomiting. She was evaluated, and was admitted to the hospital for further evaluation and treatment. She was started on her regular medications, as well as stanozolol, 6 mg PO, QD. Intermittent neck swelling occurred on several occasions during her hospitalization.  These episodes decreased in duration and intensity of the course of her 2-week hospitalization. The event was considered recovered upon discharge on 31 August2006.

 

The Investigator categorized this event as moderate and not related to the study medication.

 

Subject 13-002 SAE: Laryngeal edema

 

Subject 13-002 was a 40-year-old White female. Relevant medical history included hereditary angioedema, and gastro-esophageal reflux disease.

 

The subject had her first dose of open-label Cinryze on 26 July 2006. The subject had her first dose of randomized study drug (Placebo) on 17 August 2006 and her first dose of randomized Cinryze on 16 November 2006. Her last dose of randomized Cinryze was on 08 February 2007.

 

The subject was hospitalized at her local community hospital on 11 February 2007 for an acute, severe attack of laryngeal edema, which required intubation. This was the subject's third intubation secondary to HAE. The subject was placed on a ventilator, and was treated with 2 units of fresh frozen plasma and IV dexamethasone 20 mg; however, her condition did not improve significantly over 3 days.

 

The subject was transferred to the ----------------------- Hospital Intensive Care Unit. She had a peripherally inserted IV catheter (PICC) line placed, and received treatment with Cl esterase inhibitor. The subject's condition improved markedly in less than 48 hours. She was extubated on 16 February 2007. The subject had no further HAE episodes and was transferred to the general medical floor. The event of laryngeal edema was considered fully resolved on 19 February 2007.

 

The subject completed the study.

 

The Investigator categorized this event as severe and not related to the study medication and related to HAE.

 

 

Appendix 4:  Viral Reduction Studies

Table: Log10 Reduction Factor for Selected Viruses

 

 

 

Process Step

 

Enveloped Viruses

 

Non-Enveloped Viruses

HIV

BVDV

PRV

HAV

CPV

PEG precipitation

5.1 ± 0.2

4.5 ± 0.3

6.0 ± 0.3

2.8 ± 0.2

4.2 ± 0.2

Pasteurization

> 6.1 ± 0.2

> 6.7 ± 0.3

> 6.7 ± 0.2

2.8 ± 0.3

0.1 ± 0.3

Nanofiltration