FDA Briefing Document
`
`FDA Briefing Document
`
`Blood Products Advisory Committee Meeting
`
`May 1-2, 2008
`
`CinryzeTM (C1-esterase Inhibitor (Human) Nanofiltered (C1INH-nf)
`
`Lev Pharmaceuticals, Inc.
`
`TABLE OF CONTENTS
`
`Basil Golding, MD
`Division of Hematology
`OBRR/CBER/FDA
`
`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
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`CSL EXHIBIT 1037
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`FDA Briefing Document
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`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
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`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 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):
`
`------------------------------------------------------------------
`-------------------------------------------------------------------------------------------------------------------------------------------
`-------------------------------------------------------------------------------------------------------------------------------------------
`-----------------------------------------------------------------
`
`--------------------------------------
`----------------------------------------------------------------------------------------------------------------------------------------------
`KB2003.01
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`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:
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`(cid:1)
`
`(cid:1)
`
`(cid:1)
`
`(cid:1)
`
`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
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`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
`
`c.
`
`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.
`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.
`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.
`Subjects are monitored every 15 minutes for 8.5 hours to record response data.
`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.
`
`d.
`
`e.
`f.
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`g.
`
`h.
`
`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.
`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)
`Baseline corrected AUC(0-∞)
`(U*hr/mL)
`CL (mL/min)
`Half-life (hours)
`Mean residence time (MRT) hrs
`
`0.37 ± 0.15
`
`24.5 ± 19.1
`
`0.85 ± 1.07
`56 ± 36
`84 ± 50
`
`0.51 ± 0.19
`
`39.1 ± 19.9
`
`1.17 ± 0.78
`62 ± 38
`91 ± 52
`
`Plot of Cinryze plasma concentrations vs. time (functional C1INH activity)
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`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. --------------------------- ---------------------------------------------------------------------------------------------
`-----------------------------------------------------------
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`Table 2: Completed Safety and Efficacy Studies with Cinryze (CIINH) Conducted by Lev Pharmaceuticals, Inc.
`(Part A)
`
`study Number
`Drug
`Indication
`
`asatherapeuicagent 2000 U
`
`0 Cinryze (Ct INH-nt)
`
`ears
`
`Pl'il'lBlyZ
`Tlme to he
`begiming ot
`memivoml reliet
`
`begim'ng of relief
`within 4 hotlrs
`blkiwing
`treatment time to
`complete resolution
`of the attack;
`tlects at treatment
`on CIINH and 04
`levels.
`
`3 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 Cimyze
`treatment group in the “As Treated” population.
`
`This study was submitted to the FDA as Part A and is currently under review.
`Table 3: Completed Safety and Efficacy Studies with Cinryze (CIINH) Conducted by Lev Pharmaceuticals, Inc. (Part
`B)
`
`study
`Number
`Drug
`Indication
`
`.
`Study Destgn
`
`Dose
`
`study
`Population
`
`LEVP 2005-1
`PART/B
`Cintyze
`HAE
`
`- Phase 3, multicenter, randomized,
`placebo-controlled, double-blind cross-
`Over study to evaluate the efficacy and
`safety of Cinryze (C1lNH-nt) for
`prevention of acute attacks of HAE
`
`Cinryze: 1000 U or Randomized and 2 subjects AEs. clinical
`Placebo (2
`Treated: 24
`M: o
`laboratory. vital
`infusions per week)
`F: 2
`signs, antigenicity,
`in 2 12—week
`Placebo/Gin 2e. Age: 4I-
`viral serology
`periods
`ry
`'
`53
`12
`
`
`
`
`_
`_
`C'myzeg'acem
`.
`Efi'cacy 93‘3“”
`22 Subjects
`#2?)
`'
`
`Age:9-73
`Years
`
`'rimary:
`Number or attack or
`-. ngioedema
`
`i
`.
`. condary.
`Number or
`ithdrawals
`Total number of days
`t swelling
`Average severity of
`ttacks
`Average duration of
`2 ttacks,
`Number of open label
`inryze infusions,
`Average number of
`rays of swelling,
`fleet of treatment on
`1INH levels
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`YeaI’S
`
`Safety Dataset
`(randomized):24
`M:3
`F221
`
`Age29-73
`
`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 (ClINH) Conducted by Lev Pharmaceuticals, Inc.
`
` study
`
`Number
`Drug
`Indication
`
`.
`Study Desrgn
`
`Dose
`
`.
`
`_ Safety Data
`
`Other
`Outcomes
`
`Phase 1, randomized, parallel-
`group, open-label study to
`of Cinryze (CilNH-nt) to that of
`2 doses
`
`27 subjects
`1 dose
`(13 subjects)
`2 doses
`(14 subjects)
`M:10
`F117
`Age219—57
`Years
`
`AES, clinical
`laboratory. vital
`signs, and
`virology
`
`PK of antigenic
`and functional
`C1INH-nt:
`PK of C4
`
`This is the PK study described in the text (see above 2.23)
`
`Table 5: Ongoing Safety and Efficacy Studies with Cinryze (ClINH) Conducted by Lev Pharmaceuticals, Inc.
`
`study Number
`Drug
`Indication
`
`study Design
`
`Dose
`Duration
`
`Enrolled
`Treated
`
`Safety Data
`
`as of
`25 Sep 2007
`
`C1INH and C4 levels.
`
`67 subjects
`67 subjectsM:18
`F249
`Age: 7-81Years
`
`Ol relief within 4 l'ltllls.
`beg'nning of relief,
`change in time to the
`mequivoca begnn‘ng
`of relief
`
`LEVP 2006-1
`HAE
`
`-
`
`' se 3, mum-center, open .
`Study that will evaluate he
`(011mm) as prophylaxis to
`prevent HAE atadts
`
`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 reported a
`history of a high frequency of HAE attacks (2-3 per month) were enrolled into Part B.
`
`https://www.fda.gov/ohrms/dockets/ac/O8/briefing/2008-4355B2—1b.htm
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`FDA Briefing Document
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`Subjects in Part B were randomized to receive intravenous treatments 2 to 3 times per week for 12 weeks with 1000 U
`CinryzeTM or a matched dose ofplacebo, administered at a clinical site under a blinded clinical trial design. At the end of the
`12 week prophylaxis period, subjects were crossed over. without a washout period. to the other prophylaxis arm (CinryzeTM
`or placebo) for an additional 12 week period Subjects in either arm received open label C lINH if treated during acute
`attacks, 1000 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 12 weeks.
`
`Sponsor’s Eflieacy Analyses: Part B
`
`Primary
`
`The primary efficacy endpoint for Part B was the number of attacks of angioederna 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 eflicacy 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 ClINH-nf infusions.
`change from baseline in ClINH antigenic and fimctional levels
`
`Other Evaluations
`
`The total number of days of swelling in each study period was compared between ClINH-nf and placebo.
`
`Table 6: Part B — Results of prophylaxis of HAE attacks (11 = 22)
`
`—nn-_n-———
`m-m
`—l-IEI-_—-___
`
`n-n-lalm
`
`https://www.fda.gov/ohrms/dockets/ac/O8/briefing/2008-4355B2—lb.htm
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`FDA Briefing Document
`53-002
`2
`
`81
`
`06-018
`
`0.02
`
`9
`
`81
`
`0.1 l
`
`78%
`
`75%
`
`78%
`
`76%
`
`15 '-‘N\OC
`0000
`
`60%
`
`47%
`
`50%
`
`30%
`
`35%
`
`32%
`
`25%
`
`20%
`
`14%
`
`0%
`
`-6%
`
`60%
`
`47%
`
`43%
`
`43%
`
`32%
`
`31%
`
`25%
`
`21%
`
`10%
`
`1%
`
`-8%
`
`VI
`
`-88%
`
`-85%
`
`51-001
`
`13-002
`
`53-003
`
`18-004
`
`53-001
`
`16-0
`
`56-001
`
`52-001
`
`07-01
`
`54-001
`
`16-00
`
`17-002
`
`\l
`
`12
`
`12
`
`17
`
`The sponsor has presented these outcomes (Table 7a) 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 7a: Results of Part B — Prophylaxis
`(Sponsor’s Analysis)
`'
`e
`Cmryz
`(N‘22)
`
`awed) m-
`Number of
`
`Median
`
`Placebo
`(N=22)
`127
`
`13.5
`
`
`
`_—22
`l 7
`
`Table 7b: Results of Part B — Prophylaxis
`(Sponsor’s Analysis)
`
`Generalized Estimating Equation (GEE) Analysis Results
`
`0.3494
`
`Treannenmfrectwame
`
`Sequence Efi‘ect p—value
`
`Period Efl'ect p-value
`
`0.3347
`
`Table 7b 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 efl'ect. Sequence or period effects did not confound the results. Even if
`10/22 patients. showing aberrant C4 and/or antibody levels are excluded from the efiicacy analysis. the treatment efi‘ect was
`statistically significant (p =0.0004).
`
`As can be seen fiom Table 6. and the histogram below, treatment with CinryzeTM resulted in varying reductions in HAE
`attack fi'equency: 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.
`
`https://www.fda.gov/ohrms/dockets/ac/O8/briefing/2008-4355B2-lb.htm
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`FDA Briefing Document
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`Histogan ot the Percent Reduction ot HAE Attack Frequemywhie on
`
`CtINH Prophylaxis
`
`anH
`.—
`
`uo
`
`a=
`
`Percent Reducion in HAE Aladt Frequenq
`
`tn
`
`hoho
`
`.I:
`E:I
`2
`
`“$9
`":9 “:9 “:9 ‘% "?9 89 2,9 ‘9‘?
`”ibisf6_ '26. 316‘ lie fife?
`0% 0% €01? “be ’94? ‘2? 0% 0%
`
`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 C lINH-nf infusions, change from baseline in ClINH antigenic
`and fimctional 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 C lINH infusions - appear no