FDA Briefing Document

 

Blood Products Advisory Committee Meeting

 

May 1-2, 2008

 

 

 

 

 

 

 

 

 

Cinryze^TM (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:             Cinryze^TM

 

Product composition (from the Applicant’s proposed label):

 

Cinryze^TM 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 Cinryze^TM, C1-esterase Inhibitor (Human)  Nanofiltered (C1INH-nf) indicated for the prevention of hereditary angioedema attacks.  Cinryze^TM 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.

 

 

 

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 Cinryze^TM 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 Cinryze^TM 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 Cinryze^TM 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 Cinryze^TM.  FDA proposes postmarketing studies to evaluate this issue further.

 

Safety

 

The safety profile of Cinryze^TM 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 Cinryze^TM.  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

 

Cinryze^TM 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 Cinryze^TM appears to be acceptable.  The immunogenicity of Cinryze^TM 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 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 formed

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 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 (C_max 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 Cinryze^TM.

 

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