`
`CSL EXHIBIT 1029
`
`Page 1 of 16
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`CSL V. Shire
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`Page 1 of 16
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`CSL EXHIBIT 1029
`CSL v. Shire
`
`

`

`ALLERGY and ASTHMA PROCEEDINGS
`
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`Editor-in-Chief: Joseph A. Bellanti, MD
`Executive Editorial Board
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`Associate Editor: Russell A. Settipane, MD
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`American Board Members:
`
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`Washington, DC.
`Christopher C. Randolph, MD
`Waterbury, CT
`Diane E. Schuller, MD
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`Providence, RI
`Charles J. Siegel, MD
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`Sami L. Bahna, MD
`Shreveport, LA
`William Berger, MD
`Mission Viejo, CA
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`Cincinnati, OH
`Malcolm Blumenthal, MD
`Minneapolis, MN
`Warner W. Carr, MD
`Mission Viejo, CA
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`Sacramento, CA
`Linda S. Cox, MD
`Fort Lauderdale, FL
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`Hershey, PA
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`Winston-Salem, NC
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`Marietta, GA
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`Rockford, IL
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`Verona, Italy
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`France
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`Clim'cal Pearls and Pitfalls
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`Southampton, UK
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`W. Australia
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`Mexico City, Mexico
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`Sweden
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`Elio Novembre, MD PhD
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`Lisbon, Portugal
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`P. Pohunek, MD PhD
`Czech Republic
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`“POPS” Case Re arts
`Joseph A. Bellanti, M
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`Page 2 of 16
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`
`Participating Societies
`Alaska Allergy Society
`Maine Society of Allergy
`President: Melinda M. Rathkopf, MD
`President: Andrew B. Carey, MD
`
`Oregon Society of Allergy, Asthma
`& Immunology
`President: Justin 5. Treat, DO
`
`Pennsylvania Allergy and Asthma
`Association
`President: Mary E. Fontana-Penn, MD
`
`Rhode Island Society of Allergy
`President: Russell A. Settipane, MD
`FAAAAI
`
`South Carolina Society of Allergy,
`Asthma & Immunology
`President: John T. Rainey, MD
`
`South Dakota Allergy Society
`President: Mark Bubak, MD
`
`Southwest Allergy Forum
`Director: Agile Redmon, MD
`
`Tennessee Society of Allergy, Asthma,
`& Immunology
`President: Ty Prince, MD
`
`Texas Allergy, Asthma and
`Immunology Society
`President: Louise H. Bethea, MD
`
`Asthma and Allergy Society of
`Virginia
`President: John A. Simpson, MD
`
`Washington State Society of Allergy,
`Asthma, and Immunology
`President: Pandora E. Christie, MD
`
`Western Society of Allergy, Asthma
`82 Immunology
`President: Amy Wagelie-Steffen, MD
`
`Allergy, and Asthma Society of
`Georgia
`President: Thomas Chacko, MD
`
`Arizona Allergy and Asthma
`Society
`President: Pierre Sakali, MD
`
`Colorado Allergy and Asthma Society
`President: David Mark Fleischer, MD
`
`Connecticut Allergy Society
`President: Jason Lee, MD
`
`Eastern Allergy Conference
`Director: Russell A. Settipane, MD
`
`Florida Society of Allergy, Asthma
`and Immunology
`President: Thomas A. Lupoli, DO
`
`Greater Kansas City Allergy Society
`President: Selina A. Gierer, DO
`
`Greater Washington Allergy, Asthma
`and Immunology Society
`President: Huamia Henry Li, MD
`
`Illinois Society of Allergy, Asthma &
`Immunology
`President: Naveed Akhtar, MD
`
`Kentucky Society of Allergy, Asthma
`8: Clinical Immunology
`President: Thomas A. Glass, MD
`
`Long Island Allergy and Immunology
`Society
`President: Marcella R. Aquino, MD
`
`Louisiana Society of Allergy, Asthma
`& Immunology
`President: Erin Trahan Pratt, MD
`
`Massachusetts Allergy and Asthma
`Society
`President: Jonathan L. Bayuk, DO
`
`Michigan Allergy <3: Asthma Society
`President: Haejin Kim, MD
`
`Mid South Allergy Forum
`President: Joseph S. Fahhoum, MD
`FAAAAI
`
`Missouri Allergy and Asthma
`Association
`President: Mark L. Vandewalker, MD
`FAAAAI
`
`Nebraska Allergy, Asthma and
`Immunology Society
`President: Jaine Brownell, MD
`
`New England Allergy Society
`President: Jonathan L. Bayuk, DO
`
`New Hampshire Allergy Society
`President: Kevin J. Roelofs, MD
`
`New Jersey Allergy, Asthma and
`Immunology Society
`President: Feryal Hajee, MD
`
`New Mexico Allergy Society
`President: Michael Rupp, MD
`
`New York State Society for Asthma,
`Allergy and Immunology
`President: John V. Bosso, MD
`
`Oklahoma Allergy & Asthma Society
`President: Timothy J. Nickel, MD
`
`Orange County Society of Allergy and
`Clinical Immunology
`President: Denis J. Yoshii, DO
`
`Wisconsin Allergy Society
`President: Sameer K. Mathur, MD,
`PhD
`
`Copyright Disclosure
`
`W A
`
`llergy 8 Asthma Proceedings (ISSN 1088-5412 print, ISSN 1539-6304 online) is owned and published bi-monthly by OceanSide
`Publications, Inc., 95 Pitman Street, Providence, RI 02906. Single copies: $25 (add $5 shipping within the USA, 3512 for outside USA ad dress);
`2016 Subscriptions: $199 per year domestic, see complete price options in reader services. Email s1Ibscriptimis@ocmnsidepublrom.
`Copyright © 2016, OceanSide Publications, Inc. (401-331-2510; Fax 401-331-0223). Printed in the USA. All rights reserved. No part of this
`publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical
`photocopying, recording, or otherwise, without prior written permission from the publisher. Statements and opinions expressed in articles
`and communications herein are those of the author(s) and not necessarily those of the Editor(s), publisher, the American Association of
`Certified Allergists (AACA), or the affiliated regional, state, and local allergy societies. The Editor(s), publisher, the American Association of
`Certified Allergists (AACA), and the affiliated regional, state, and local allergy societies disclaim any responsibility or liability for such
`material and do not guarantee, warrant, or endorse any product or service in this publication, nor do they guarantee any claim made by the
`manufacturer of such product or service. To get permission to use copyrighted material from this publication, contact Beth Ann Rochelcau
`at brocheleau@rocl<waterinc.com.
`
`Page 3 of 16
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`Page 3 of 16
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`

`

`TABLE OF CONTENTS
`
`Vol. 37, No. 6
`November—December 2016
`
`
`
`423
`
`426
`
`432
`
`439
`
`443
`
`450
`
`Editorial
`
`A Janus tale of the two faces of corticosteroid therapy: A potential for adverse effects versus
`a steroid-sparing benefit of certain therapies
`J. A. Bellanti and R. A. Settipane
`
`Reviews
`
`Intravenous and subcutaneous immunoglobulin G replacement therapy
`F. A. Bonilla
`
`Chronic obstructive pulmonary disease phenotypes, biomarkers, and prognostic indicators
`C. E. Brightling
`Utility of component diagnostic testing in guiding oral food challenges to milk and egg
`J. Wang
`Association of allergy/immunology and obstructive sleep apnea
`C. J. Calais, B. D. Robertson, and D. E. Beakes
`Clinical and etiologic evaluation of the children with chronic urticaria
`D. Azkur, E. Civeiek, M. Toyran, E. D. Mislrlioglu, M. Erkocoglu, A. Kaya, E. Vezir, T. Ginis, A. Akan,
`and C. N. Kocabas
`__~____—_______________——————
`
`Original Articles
`458 Corticosteroid-related toxicity in patients with chronic idiopathic urticaria—chronic
`spontaneous urticaria
`D. Ledford, M. S. Broder, E. Antonova, T. A. Omachi, E. Chang, and A. Luskin
`466 New insights into treatment of children with exercise-induced asthma symptoms
`I. Stelmach, A. Sztafir’lska, J. Jerzynska, D. Podlecka, P. Majak, and W. Stelmach
`475 A comparison of seasonal trends in asthma exacerbations among children from geographic regions
`with different climates
`J. A. Wisniewski, A. P. McLaughlin, P. J. Stcnger, J. Pattie, M. A. Brown, J. M. El—Dahr, T. A. E. Platts-Mills,
`N. J. Byrd, and P. W. Heymann
`482 What is the clinical value of negative predictive values of skin tests to iodinated contrast media?
`S. Soyyigit, O. Goksel, O. Aydm, Z. Gengtiirk, and S. Bavbek
`489 Subcutaneous administration of human C1 inhibitor with recombinant human hyaluronidase in
`patients with hereditary angioedema
`M. A. Riedl, W. R. Lumry, H. H. Li, A. Banerji, J. A. Bernstein, M. Bas, J. Bjorkander, M. Magerl, M. Maurer,
`
`K. Rockich, H. Chen, and J. Schranz
`
`Clinical Pearls and Pitfalls
`
`501 Idiopathic CD4 lymphocytopenia
`
`J. P. Brooks and G. Ghaffari
`
`Reader Service
`505 For the Patient: Seasonal trends in asthma exacerbations among children from different geographic
`regions
`J. A. Bellanti and R. A. Settipane
`
`
`
`Online Articles—www.allergyandasthmaproceedings.c0m
`506 Measures to reduce maintenance therapy with oral corticosteroid in adults with severe asthma
`(e125)
`V. Q. Nguyen and C. S. Ulrik
`506 Hygiene factors associated with childhood food allergy and asthma
`(e140)
`R. S. Gupta, A. M. Singh, M. Walkncr, D. Caruso, P. J. Bryce, X. Wang, J. A. Pongracic, and B. M. Smith
`506 Effects of the addition of tiotropium on airway dimensions in symptomatic asthma
`M. Hoshino, J. Ohtawa, and K. Akitsu
`(e147)
`
`Page 4 of 16
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`Page 4 of 16
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`

`

`Subcutaneous administration of human C1 inhibitor with
`recombinant human hyaluronidase in patients with
`hereditary angioedema
`
`Marc A. Riedl, M.D., M.S.,1 William R. Lumry, M.D.,2 H. Henry Li, M.D., Ph.D.,3
`Aleena Banerji, M.D., Phil,4 Jonathan A. Bernstein, M.D.,5 Murat Bas, M.D.,6
`Janne Bjorkander, M.D., Ph.D.,7 Markus Magerl, M.D.,8 Marcus Maurer, M.D.,8 Kevin Rockich, Ph.D.,9
`Hongzi Chen, Ph.D.,9 and Jennifer Schranz, MD.9
`
`ABSTRACT
`
`Background: The currently approved method of C1 inhibitor (C1 INH) administration for patients with hereditary
`arzgioedema with C1 INH deficiency (HAE) is by intravenous injection. A C1 INH subcutaneous formulation may provide an
`attractive mode of administration for some patients.
`Objective: To evaluate efficacy and safety of two doses of subcutaneous, plasma-derived C1 INH with the dispersing agent.
`recombinant human hyaluronidase (rHuPHZO) to prevent angioedema attacks in patients with HAE.
`Methods: A randomized, double-blind, dose-ranging, crossover study, patients 2 12 years of age (it = 47) with a confirmed
`diagnosis of HAE were randomly assigned to receive subcutaneous injections of 1000 Ll C1 INH with 24,000 Ll rHuPHZO 0”
`2000 U C1 INH with 48,000 LI rHuPHZO every 3 or 4 days for 8 weeks and then crossed—over for another 8—week period. The
`primary efi‘icacy end point was the number of angioedema attacks during each treatment period.
`Results: The study was terminated early as a precaution related to non-neutralizing antibodies to rHaPHZO in 45% of
`patients. The mean i standard deviation number of angioedema attacks during the 8-week treatment periods were 1.58 i 1.59
`with 1000 L1 C1 INH and 0.97 i 1.26 with 2000 U. The mean (95% confidence interval [Cl]) within—patient diflerence (2000
`U—1000 Ll, respectively) was ~0.61 (95% Cl, —1.23 to 0.01) attacks per month (p = 0.0523), and —0.56 (95% CI, -1.06 10
`—0.05) attacks that required acute treatment, (p = 0.0315). No deaths or other serious adverse events were reported.
`Injection—site reaction was the most common adverse event.
`Conclusion: Despite early termination, this study demonstrated a clinically and statistically significant differenCe in burden
`of disease, which favored 2000 U C1 INH, without associated serious adverse events.
`(Allergy Asthma Proc 37:489—500, 2016; doi: 10.2500/aap2016-37-4006)
`
`489
`
`HAE experience recurrent, unpredictable angioedema
`ereditary angioedema with C1 INH deficiency
`attacks, which most commonly affect the mucosa of the
`(HAE) is a rare disease caused by mutation in
`gastrointestinal tract and the skin of the extremlties
`the C1 INH gene, which results in deficient levels or
`and face.‘2 The severity of the attacks can be variable,
`functionality of the C1 INH protein.1 Patients with
`
`
`
`From the 1Division of Rlieumntology, Allergy and Immunology, US HAE/i Angio—
`edema Center, University of California—San Diego School of Medicine, La lolla,
`California, {Allergy and Asthma Research Associates Research Center, Dallas, Texas,
`3Institutefor Asthma and Allergy, Chevy Chase, Maryland, *Department ofMedicine,
`Allergy 5* Clinical Immunology, Massachusetts General Hospital, Boston, Massachu-
`setts, 5Dcpartment of Medicine, Innnunology and Allergy, University of Cincinnati
`Medical Center, Cincinnati, Ohio, 6Department of Otorhinolaryngology, chhnische
`Universititt Munchcn, Munich, Germany, 7Futuruni Academy for Health and Care,
`Region [onko'ping County, Iiinko‘ping, Sweden, ‘Department of Dermatology and
`Allergy, Clmrite—Liniversitatsmedizin Berlin, Germany, and 95hire, Wayne, Penn-
`sylvania
`This study was sponsored by ViroPharnia Incorporated, now part of the Shire Group
`of Companies
`MA. Ricdl has received research grants from Dyax, Shire, ViroPharma (now part of
`the Shire Group of Companies), CSL Behring, BioCryst, and Santarus; consultantfees
`from Dyax, Shire, CSL Behring, Biocryst, and Isis; payments for lectures from Dyax,
`Shire, ViroPharma, and CSL Behring; and is a member of the medical advisory board
`of the US Hereditary Angioedema Association. W.R. Lumry has received consultant
`fees from Dyax, Shire, ViroPharma (now part of the Shire Group of Companies), CSL
`Behring, and BioCryst; research grantsfrom Dyax, Shire, CSL Behring, and BioCryst;
`and payments for lectures from Dyax, Shire, and CSL Behring; and is a member of the
`medical advisory board of the US Hereditary Angioedema Association. H.H. Li has
`
`received consultant fees from Shire, ViroPharma (now part of the Shire Group of
`Companies), Pharming, Snntarus, and Salix; research grants from Dyax, Shire,
`ViroPharma, CSL Behring, Pharming, Salix, and BioCryst; and paymentsfor lectures
`from Dyax, Shire, ViroPhar-ma, and CSL Behring; and is a member of the medical
`advisory board of the US Hereditary Angioedema Association, A. Banerji has received
`research grants and consultant fees from Dyax, Shire, ViroPharma ("011) part of flu'
`Shire Group of Companies), and CSL Behring,- and is a member ofthe medical advisory
`board of the US Hereditary Angioedema Association. lA. Bernstein has received
`consultant fees from Dyax, Shire, CSL Behring, and ViroPharnza (now part of the
`Shire Group of Companies); research grants from Bl, Forest, Virol’harnza, CSL
`Behring, Dyax, Shire, Pharming, and Novartis; paymentfor lecturesfrom Shire, Teva,
`Dyax, ViroPharma, and CSL Behring; payment for the development of educational
`presentations from Shire, ViroPharma, and Medscape; and is a member of the medical
`advisory board of the U5 Hereditary Angioedema Association. M. Bas has received
`consultant fees, research grants, and payment for lectures from Shire; and has also
`received research grantsfrom ViraPharma (now part of the Shire Group ofCompanies)
`and Plzarming. ]. Bfo‘rkander has participated in advisory boards for Baxter, Octop-
`harma, and CSL Behring; received research grants from CSL Behring and Viro-
`Pharma; and worked as consultant for Astra~checa, CSL Behring, Shire and Viro-
`Pharma. M. Magerl has received consultant fees and payment for lectures from
`BioCryst, CSL Behring, Shire, Sobi, and ViroPharma (now part of the Shire Group of
`Companies); and has received research grants from ViroPharma. M. Maurer has
`
`Allergy and Asthma Proceedings
`
`Page 5 of 16
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`

`

`but these attacks are potentially life threatening when
`localized to the upper respiratory tract.3'4 The safety
`and efficacy of intravenous (IV) administration of hu-
`man plasma—derived C1 INH for the routine preven-
`tion of angioedema attacks in patients with HAE was
`previously evaluated and approved by regulatory
`agencies.5‘B Self—administration of IV C1 INH is ap-
`proved and has been shown to be feasible and benefi-
`cial,9'10 with patients reporting satisfaction in manag—
`ing their condition in the home setting.“ However,
`more convenient modes of delivery for patients need to
`be investigated. Medication repeatedly administered
`by the IV route may be problematic when peripheral
`IV access is limited or for patients in whom IV admin-
`istration is not a Viable option. Complications at the
`injection site after IV dosing may also present concerns
`for some patients.”'13 Subcutaneous (SC) administra—
`tion of C1 INH for patients with HAE would be an
`attractive, convenient treatment alternative.”—17
`Despite practical advantages, SC administration of
`medication is limited by the dense extracellular matrix
`of the SC tissues. Recombinant human hyaluronidase
`(rI-IuPHZO) (Hylenex; Halozyme Therapeutics, San Di-
`ego, CA) is a tissue permeability modifier that can
`assist dispersion of a coadministered therapeutic agent
`and potentially improve bioavailability.18'20 Clinical
`trials that evaluated the tolerability of coadministration
`of rHuPHZO and a variety of therapeutics, including
`immunoglobulin G,21
`insulin,22 ceftriaxone,23 mor—
`phine,24 ondansetron,25 and trastuzumab26 have been
`reported. This study was designed to evaluate the ef-
`ficacy, safety, tolerability, pharmacokinetics (PK), and
`immunogenicity of two SC doses (1000 U and 2000 U)
`of C1 INH coadministered with rHuPHZO (24,000 U
`and 48,000 U, respectively) to prevent angioedema at—
`tacks in patients with HAE.
`
`November—December 2016, Vol. 37, No. 8
`
`METHODS
`
`The study was performed in accordance with the
`Declaration of Helsinki and the Tripartite Guidelines
`for Good Clinical Practice of the International Code of
`
`Harmonization. All the patients provided written in-
`
`
`
`received research grants support, consultant fees, and/or payment for lectures from
`BioCryst, CSL Behring, Dyax, Shire, anti Vimlerma (now part of the Shire Group
`of Companies). K. Ruck/ch is an employee ofSliire (formerly Viropharma). H. Chen is
`an employee of Shire (formerly ViroPlIarma) and owns Shire stock/options. ]. Schmnz
`is an employee of Shire (formerly Virol’harma) and owns Shire stock/options
`Presented at the American Academy of Allergy, Asthma and Immunology, Houston,
`Texas, February 20-24, 2015; and as encore poster at the 9th C1 Inhibitor Deficiency
`Workshop, Budapest, Hungary, May 28 ~31, 2015.
`Address correspondence to Marc Riedl, MD, Division ofRheumatology, Allergy and
`Immunology, University of California—San Diego School of Medicine, La jolla, CA
`92122
`E—mail address: 11zrieril@ucsd.edzt
`Copyright © 2016, Oceanside Publications, Inc, Ll.S.A.
`
`formed consent. The ClinicalTrials.gov identifier is
`NCT01756157.
`
`Patients
`
`The patients were 212 years of age, with a confirmed
`diagnosis of HAE and a history of C1 INH antigen
`level or functional C1 INH level below normal. The
`
`patients who were receiving prophylactic IV C1 INH
`were included provided that,
`in the 3 consecutive
`months before randomization, they reported an aver-
`age angioedema attack rate of $1.0 moderate or severe
`attacks per month, and, during the 3 consecutive
`months before initiating C1 IN[-1 prophylaxis, they re-
`ported an average of 22.0 moderate or severe angio-
`edema attacks per month. Patients who were not re—
`ceiving prophylactic IV C1 INH therapy were included
`if they had an average of 22.0 moderate or severe
`angioedema attacks per month in the 3 consecutive
`months before randomization.
`
`Patients were excluded if they had received C1 INH
`therapy or blood products for treatment or prevention
`of an angioedema attack within 7 days before the first
`dose of study medication, had angioedema attack signs
`or symptoms within 2 days before the first dose of
`study medication, and / or had been receiving prophy-
`lactic IV C1 INH that exceeded the approved dosage of
`1000 U every 3 or 4 days (maximum weekly dose of
`2000 U). Additional exclusion criteria included andro-
`gen therapy within 7 days of the first dose of study
`medication, diagnosis of acquired angioedema, history
`of hypercoagulability, known allergies to C1 INH or
`hyaluronidase, pregnancy, or breast-feeding.
`
`Study Design
`
`This was a phase II, randomized, double—blind, dose-
`ranging,
`two-period,
`two-treatment crossover study
`conducted at 20 sites in the United States and at 4 sites
`in Europe (France, Germany, Spain, and Sweden). Each
`patient was to participate in two 8-week treatment
`periods, separated by a washout period of 27 days but
`<30 days. The patients were randomly assigned to one
`of two treatment sequences (period 1/2: A/ B or B/ A)
`as follows: 1000 U C1 INH with 24,000 U rHuPHZO
`(treatment A) and 2000 U C1 INH with 48,000 U
`rHuPHZO (treatment B). C1 INH was supplied as a
`lyophilized powder (500 U per vial) to be reconstituted
`with sterile water for injection,- rHuPHZO was supplied
`ready to use in 12,000 U vials. All treatments were
`prepared by unblinded study personnel at the investi-
`gational site or by home health professionals. To main-
`tain the study blinding, both treatments were admin—
`istered as a single 20 mL SC injection in the abdomen
`every 3 or 4 days at a steady rate as tolerated by the
`patient (~5 to 10 minutes). A 24-gauge SC needle in—
`jection set with 1-mm tubing diameter was used for the
`
`Page 6 of 16
`
`

`

`vast majority of injections. During the first 8-week
`period, all the treatments were administered SC by
`study personnel at the investigational site, or by home
`health professionals, who remained blinded to the
`treatment sequence and dose. During the second
`8-week period,
`the patients were allowed to self-
`administer the blinded study drug after appropriate
`training and under the supervision of the study site.
`The patients were encouraged to treat all breakthrough
`attacks during the study by using their preferred drug
`for attack treatment (e.g., icatibant SC or C1 INH con-
`centrate IV).
`
`Study Assessments
`
`of anti—C1 INI-I and anti-rHuPH20 antibodies. Post-
`baseline titers of >120 for anti-rHuPHZO antibodies
`
`were defined as a laboratory event of special interest
`and were to be reported by the sponsor to the appro-
`priate regulatory authorities. Anti—C1 INH antibodies
`were measured by Sanquin Diagnostic Services (Am-
`sterdam, the Netherlands), and anti-rHuPHZO antibod-
`ies were measured by EMD Millipore (St Charles, MO).
`Samples positive for anti-rHuPHZO antibodies were
`further analyzed for the presence of rHuPHZO neutral—
`izing activity (MicroConstants, San Diego, CA).
`
`Safety Assessment. The number and type of adverse
`events (AE5) and drug-related AEs (as assessed by the
`study investigators) were recorded and coded by using
`the Medical Dictionary for Regulatory Activities Ver-
`sion 16.0. Angioedema attacks during treatment and
`injection-site reactions (ISR), observed in the hour im-
`mediately after dosing, were specifically elicited on the
`case report form and reported as AEs. Additional mea—
`sures included changes in vital signs, clinical labora—
`tory values, and 12-lead electrocardiogram.
`
`Statistical Analyses. The intent-to—treat safety (ITT-S)
`population comprised all randomized patients who
`received at least one dose of study drug. The ITT
`efficacy (ITT—E) population comprised all the patients
`who completed both treatment periods. Approxi-
`mately 40 patients were planned to be enrolled with
`the target of achieving 34 patients who completed both
`treatment periods. Based on the results of an earlier
`crossover study of N treatment,5 the study was de—
`signed to provide 80% power to detect a significant
`difference between treatments, with a type I error rate
`of 5%. Summary statistics were provided for the pri-
`mary and secondary end points by using the ITT-E
`population. In addition, the between-treatment com-
`parison by using the analysis of variance model and
`the within—treatment comparison by using paired t-test
`were also performed for all primary and secondary
`end points for 1000 U versus 2000 U SC C1 INH.
`
`RESULTS
`
`Fifty-two patients were screened, and 47 were ran-
`domly assigned to treatment. The study was termi-
`nated early by the sponsor as a precaution related to
`the unexpected incidence and titer of non-neutralizing
`antibodies to rHuPHZO in 45% of the patients. Due to
`the early termination of the study, the final sample size
`of the ITT-E population (22/47 [47%]) was smaller than
`planned (Fig. 1). The ITT-S population included all 47
`randomized patients (Fig. 1). Patient demographics
`and baseline angioedema attack history are described
`in Table 1. At the time of enrollment, 20 of 47 patients
`(43%) were receiving IV C1 INI—i prophylaxis. Thirteen
`
`Efi‘icacy. The frequency and severity of HAE symp-
`toms and/ or attacks were captured in study diaries
`reviewed by the study investigators. Baseline angio-
`edema attack rates were estimated based on patients’
`recall and medical records of frequency, severity, and
`duration of attacks. The primary efficacy outcome mea-
`surement was the normalized number of angioedema
`attacks during each treatment period, computed as the
`number of attacks per month (i.e., 30.4 days) of expo-
`sure (number of attacks per month 2 30.4 X [number
`of attacks during treatment period]/ [days of treatment
`period]). Four secondary efficacy outcome measure-
`ments (normalized) included the following: cumula-
`tive attack severity (defined as the sum of the maxi-
`mum symptom severity recorded for each angioedema
`attack during the treatment period), cumulative daily
`severity (defined as the sum of the severity scores
`recorded for every day of reported symptoms during
`the treatment period), cumulative symptomatic days
`(defined as the sum of the symptomatic days of each
`angioedema attack reported during the treatment pe-
`riod), and the number of angioedema attacks that re-
`quired acute treatment during the treatment period.
`
`491
`
`PK. Blood samples were taken before dose 1, 2, 6, 10,
`15, and 16 of both periods, and at 24, 48, 72, and 168
`hours after dose 16. PK parameters were determined
`by using noncompartmental analysis methods based
`on the observed and baseline-corrected plasma concen-
`tration—time profiles for antigenic and functional C1
`INH, and summarized by treatment by using descrip-
`tive statistics. Individual trough or predose concentra-
`tions (Cmin) were listed and summarized by close num—
`ber by using the same descriptive statistics. PK
`analyses were performed by PharSight
`(Mountain
`View, CA) by using SAS (Cary, NC) (v9.3 or higher).
`
`Immunogenicity. Blood samples taken in each treat-
`ment period before dose 1, 8 (rHuPHZO only), and 16,
`and at 1 week after treatment and 30 t 2 days after the
`last dose of study drug were analyzed for the presence
`
`Allergy and Asthma Proceedings
`
`Page 7 of 16
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`

`10 (42%) completed treatment
`14 (58%) did not complete treatment
`10 (39%) sponsor decision
`2 (8%) patient withdrawalci"
`1 (4%) physician decision“
`1 (4%) Iostto follow-up'
`
`
`22 patients completed both treatment periods: lTT-E
`‘
`Figure 1. Patient flow diagram. C1 INH = C1 Inhibitor; lTT—S = intent—to-treat safety (all randomized patients who received at least one
`dose of study drug); ITT—E = intent-to—treat eflicacy (all patients who completed both treatment periods); rHuPH20 = recombinant human
`hyaluronidase. “The patient discantinued the study drug (on day 8 after three doses) due to unwillingness to continue because of logistical
`issues with the home health agency; dismntinued from study on day 44. leie patient discontinued the study drug (on day 72, which was
`day 11 of period 2, after 11 doses) due to poor compliance. cThe patient discontinued the study drug (on. day 1 after one dose) due to wanting
`to resume regular prophylactic treatment dThe patient discontinued the study drug (on day 8 after three doses) and, subsequently, was lost
`to follow-up after early termination visit, and was discontinued from the study on day 43. 0The patient had moderate extremity attacks on
`days 46 and 48, and severe gastrointestinal and/or abdominal attacks on day 60 (during washout), each attack required treatment with
`icatibant acetate; the patient also received acute treatment for angioedema attacks with multiple doses of danazol on day 50,- the patient
`discontinued the study drug on day 67 (day 4 of period 2) after 18 doses, and had a moderate extremity attack on day 70, 3 days after the
`last dose of study drug; during the 3 months before randomization, this patient had had a total of six attacks. fThe patient discontinued the
`study drug and the study (on day 1 after one dose) due to being lost to follow—up.
`
`November—December 2016, Vol. 37, No. 6
`
`
`
`
`
`
`12 (52%) completed treatment
`11 (48%) did not complete treatment
`9 (39%) sponsor decision
`1 (4%) patient withdrawala
`1 (4%) physician decisionb
`
`of these patients completed both treatment periods,
`thus 13 of 22 of the ITT-E population (59%) received
`previous c1 INH prophylaxis therapy.
`
`Efficacy
`Twice-weekly SC administration of 1000 U C1 INH
`plus 24,000 U rHuPH20 and 2000 U C1 INH plus
`48,000 U rHuPH20 resulted in statistically significant
`reductions in the frequency of angioedema attacks
`compared with baseline (Table 2). The mean percent-
`age change from baseline in the normalized number of
`angioedema attacks during treatment was ~-50% and
`—73% for the 1000- and 2000-U doses, respectively. A
`numerically greater reduction from baseline in the nor-
`malized number of angioedema attacks was seen in the
`2000-U dose (—3.24) compared with the 1000-U dose
`(—2.63) (Table 2); however, the difference between the
`doses was not statistically significant (p = 0.068).
`Results that numerically favored the 2000 U SC
`C1 INH dose were observed for primary and all sec-
`ondary efficacy end points during treatment for the
`two-sample comparison by using an analysis of vari-
`ance model (Table 2); however, no statistical differ-
`ences were observed between the 1000 U and 2000 U
`SC C1 INH doses in the treatment comparison for any
`
`end point. The mean normalized number of angio-
`edema attacks during treatment (primary end point)
`was lower for the 2000 U SC C1 INH dose (0.97)
`compared with the 1000 U SC C1 INH dose (1.58), with
`attack frequency reduced by 0.6 attacks per month at
`the higher C1 INH dose level. For secondary end
`points, lower cumulative attack severity, daily severity,
`and number Of symptomatic day scores; as Well as
`fewer attacks that required acute treatment, were ob—
`served during treatment with the 2000 U versus the
`1000 U SC C1 INH dose.
`Within-subject analysis revealed no sequence effect
`for primary and secondary efficacy outcomes (Table 3).
`For the primary efficacy end point, the normalized
`number of angioedema attacks during treatment was
`numerically higher for patients who received 1000 U
`compared with 2000 U; statistically, the treatment dif-
`ference was not significant (p = 0.0523). For the sec-
`ondary end points, statistically significant within—
`patient treatment effects that favored the 2000-U dose
`compared with the 1000-U dose were observed for
`cumulative attack severity (p = 0.0277) and the number
`of attacks that required acute treatment (p = 0.0315)
`(Table 3). Differences in cumulative daily severity and
`cumulative symptomatic days favored the 2000-U dose
`
`492
`
`52 patients screened
`
` V
`
`5 excluded
`4 did not meet eligibility criteria
`1 withdrew consent
`
`47 patients randomized to Treatment Sequence (A/B or B/A): lTT-S
`A: 1000 U C1 INH with 24,000 U rHuPH20
`B: 2000 U C1 INH with 48,000 U rHuPH20
`
`
`
`.J
`23 patients: Sequence N8
`
`24 patients: Sequence B/A
`
`Page 8 of 16
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`

`Table 1 Patient demographics and disease characteristics
`
`Treatment Group and Sequence
`
`A11 Patients
`
`Treatment A, Washout,
`Treatment B
`
`Treatment B, Washout,
`Treatment A
`
`24
`
`47
`
`38.3 i- 15.7
`
`36.0 (16, 66)
`
`39.0 i 14.6
`
`39.0 (16, 66)
`
`1 (4)
`15 (63)
`7 (29)
`1 (4)
`
`18 (75)
`6 (25)
`
`